Body-protective compound (BPC) 157 demonstrates protective effects against damage to various organs and tissues. For future clinical applications, we had previously established a solid-phase synthesis process for BPC157, verified its biological activity in different wound models, and completed preclinical safety evaluations. This study aimed to investigate the pharmacokinetics, excretion, metabolism, and distribution profiles of BPC157. After a single intravenous (IV) administration, single intramuscular (IM) administrations at three doses in successive increments along with repeated IM administrations, the elimination half-life (t1/2) of prototype BPC157 was less than 30 min, and BPC157 showed linear pharmacokinetic characteristics in rats and beagle dogs at all doses. The mean absolute bioavailability of BPC157 following IM injection was approximately 14%–19% in rats and 45%–51% in beagle dogs. Using [3H]-labeled BPC157 and radioactivity examination, we proved that the main excretory pathways of BPC157 involved urine and bile. [3H]BPC157 was rapidly metabolized into a variety of small peptide fragments in vivo, thus forming single amino acids that entered normal amino acid metabolism and excretion pathways. In conclusion, this study provides the first analysis of the pharmacokinetics of BPC157, which will be helpful for its translation in the clinic.
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Pharmacokinetics, distribution,
metabolism, and excretion of
body-protective compound 157,
a potential drug for treating
various wounds, in rats and dogs
Lei He
1†
, Donglin Feng
1
,
2†
, Hui Guo
2
, Yueyuan Zhou
1
,
Zhaozhao Li
1
, Kuo Zhang
1
, Wangqian Zhang
1
, Shuning Wang
1
,
Zhaowei Wang
1
, Qiang Hao
1
, Cun Zhang
1
, Yuan Gao
1
,
Jintao Gu
1
, Yingqi Zhang
1
, Weina Li
1
* and Meng Li
1
*
1
State Key Laboratory of Cancer Biology, Department of Biopharmaceutics, School of Pharmacy, Air
Force Medical University, Xi’an, China,
2
School of Pharmacy, Shaanxi University of Chinese Medicine,
Xi’an, China
Body-protective compound (BPC) 157 demonstrates protective effects against
damage to various organs and tissues. For future clinical applications, we had
previously established a solid-phase synthesis process for BPC157, verified its
biological activity in different wound models, and completed preclinical safety
evaluations. This study aimed to investigate the pharmacokinetics, excretion,
metabolism, and distribution profiles of BPC157. After a single intravenous (IV)
administration, single intramuscular (IM) administrations at three doses in
successive increments along with repeated IM administrations, the
elimination half-life (t
1/2
) of prototype BPC157 was less than 30 min, and
BPC157 showed linear pharmacokinetic characteristics in rats and beagle
dogs at all doses. The mean absolute bioavailability of BPC157 following IM
injection was approximately 14%–19% in rats and 45%–51% in beagle dogs.
Using [
3
H]-labeled BPC157 and radioactivity examination, we proved that the
main excretory pathways of BPC157 involved urine and bile. [
3
H]BPC157 was
rapidly metabolized into a variety of small peptide fragments in vivo, thus
forming single amino acids that entered normal amino acid metabolism and
excretion pathways. In conclusion, this study provides the first analysis of the
pharmacokinetics of BPC157, which will be helpful for its translation in the clinic.
KEYWORDS
BPC157, pharmacokinetics, absorption, distribution, metabolism, excretion, wounds
OPEN ACCESS
EDITED BY
Junmin Zhang,
Lanzhou University, China
REVIEWED BY
Yurong Lai,
Gilead, United States
Mei-Hua Qu,
Weifang Second People’s Hospital,
China
*CORRESPONDENCE
Weina Li,
Meng Li,
†
These authors have contributed equally
to this work
SPECIALTY SECTION
This article was submitted to Drug
Metabolism and Transport,
a section of the journal
Frontiers in Pharmacology
RECEIVED 23 August 2022
ACCEPTED 23 November 2022
PUBLISHED 14 December 2022
CITATION
He L, Feng D, Guo H, Zhou Y, Li Z,
Zhang K, Zhang W, Wang S, Wang Z,
Hao Q, Zhang C, Gao Y, Gu J, Zhang Y,
Li W and Li M (2022), Pharmacokinetics,
distribution, metabolism, and excretion
of body-protective compound 157, a
potential drug for treating various
wounds, in rats and dogs.
Front. Pharmacol. 13:1026182.
doi: 10.3389/fphar.2022.1026182
COPYRIGHT
© 2022 He, Feng, Guo, Zhou, Li, Zhang,
Zhang, Wang, Wang, Hao, Zhang, Gao,
Gu, Zhang, Li and Li. This is an open-
access article distributed under the
terms of the Creative Commons
Attribution License (CC BY). The use,
distribution or reproduction in other
forums is permitted, provided the
original author(s) and the copyright
owner(s) are credited and that the
original publication in this journal is
cited, in accordance with accepted
academic practice. No use, distribution
or reproduction is permitted which does
not comply with these terms.
Frontiers in Pharmacology frontiersin.org01
TYPE Original Research
PUBLISHED 14 December 2022
DOI 10.3389/fphar.2022.1026182
1 Introduction
Body-protective compound (BPC) 157 is a peptide isolated
from human gastric juice (Sikiric et al., 1993).
BPC157 comprises 15 amino acids (Gly-Glu-Pro-Pro-Pro-
Pro-Gly-Lys-Pro-Ala-Asp-Asp-Ala-Gly-Leu-Val) and has a
molecular weight of 1419 Da. Also known as BPC-15, PL-10,
PLD-116, or PL14736 (Keremi et al., 2009), BPC157 has
demonstrated remarkable potential as a therapeutic agent for
severe trauma and stress damage and can promote the healing
of wounds, ligament injuries, tendon injuries, and fractures.
BPC157 exerts a significant protective effect on various tissues
and organs, such as the esophagus, stomach, duodenum (Drmic
et al., 2017), colorectal mucosa (Duzel et al., 2017), liver,
pancreas (Konturek and Brzozowski, 2008), muscle (Lai
et al., 2019), cornea (Lazic et al., 2005), heart (Sikiric et al.,
2016) and nerves (Grabarevic et al., 1997;Klicek et al., 2013;
Wang et al., 2019). Apart from its protective effect against
multiple organ injuries, BPC157 has also demonstrated
cytoprotective (Sikiric et al., 2018) and anti-inflammatory
properties and plays a role in maintaining epithelial integrity
(Mota et al., 2018). Although the mechanism of action of
BPC157 remains unclear, BPC157 has demonstrated
significant effects at very low doses with very good stability
(Sikiric et al., 2018). It can be stored at room temperature and is
resistant to hydrolysis, enzyme digestion, and even gastric juice.
Based on the stability and pleiotropy of BPC157, it is an ideal
candidate for the treatment of all types of severe trauma and
may be superior to the widely used cytokine drugs in wound
therapy.
Previously, we established a solid-phase synthesis process
for BPC157 (Xue et al., 2004)andverified its biological activity
in rat gastric ulcer models and various skin wound models
(Huang et al., 2015). At the same time, our preclinical safety
evaluation studies showed that BPC157 was well tolerated and
did not demonstrate any serious toxic effects in mice, rats,
rabbits, or dogs (Xu et al., 2020). For evaluating its future
clinical use as a therapeutic drug and follow-up clinical trials,
the present study was undertaken to evaluate the
pharmacokinetics, tissue distribution, metabolism, and drug
excretion of BPC157 in Sprague-Dawley (SD) rats and beagle
dogs as well as in associated in vitro studies. The experiments
were performed according to the criteria of the new
investigational drug application. This study is the first
preclinical pharmacokinetic study of BPC157, and the results
are of considerable importance, as they demonstrate not only
the pharmacokinetic parameters of BPC157 but also show the
implications for its systemic application as a novel drug for
various injuries.
2 Results
2.1 Pharmacokinetic studies of BPC157 in
rats
The effective dose of BPC157 for the treatment of various
injuries in mice, rats, and rabbits ranges from 6 to 50 μg/kg
(Huang et al., 2015;Mota et al., 2018;Sikiric et al., 2018). Our
proposed clinical dose of BPC157 was 200 μg/person/day, and its
equivalent dose in rats was 20 μg/kg (converted based on body
surface area). Therefore, we performed pharmacokinetic studies
of BPC157 in rats following a single intravenous (IV)
administration of 20 μg/kg, single intramuscular (IM)
administration of doses 20, 100, or 500 μg/kg, and repeated
IM administrations of 100 μg/kg of BPC157 for seven
consecutive days. The administration of BPC157 was well
tolerated by all rats, and no visual signs of toxicity were
observed, consistent with our previous safety evaluation
studies (Xu et al., 2020). In addition, no noticeable difference
in the plasma concentration of BPC157 was observed between
male and female rats.
The mean (+SD) plasma concentration of BPC157 versus
time curves following administration of various BPC157 doses in
rats are shown in Figures 1A–C, and the corresponding
pharmacokinetic parameters are presented in Tables 1–Tables
3. After a single IV administration, BPC157 was rapidly
eliminated from the plasma of rats, and the average
elimination half-life (t
1/2
) was 15.2 min. The average area
under the plasma concentration-time curve (AUC
0–t
) was
399 ng min/ml. After single IM administrations of doses 20,
100, or 500 μg/kg, the peak time (T
max
) of each dose was
3 min. The maximum concentrations (C
max
) of each dose
were 12.3, 48.9, and 141 ng/ml, respectively, and the AUC
0–t
values were 75.1, 289, and 1930 ng min/ml, respectively. Linear
relationships were observed between AUC
0–t
and BPC157 doses,
as well as between C
max
and BPC157 doses (Figures 1D,E). The
absolute bioavailability after IM administration of each dose was
18.82%, 14.49%, and 19.35%, respectively. After repeated IM
administration of BPC157 at 100 μg/kg for seven consecutive
days, the plasma concentration versus time curve (Figure 1C) and
pharmacokinetic parameters (Table 3) were similar to those
observed after a single IM injection at a dose of 100 μg/kg,
except for a slight increase in C
max
and AUC
0–t
. The
aforementioned results showed that BPC157 reached its peak
rapidly in rats and was rapidly eliminated after reaching its peak.
The prototype drug could not be detected 4 h after
administration, and its elimination half-life was less than
30 min. BPC157 showed linear pharmacokinetic characteristics
in rats at the experimental dose.
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He et al. 10.3389/fphar.2022.1026182
2.2 Pharmacokinetic studies of BPC157 in
beagle dogs
Our proposed clinical dose of BPC157 was 200 μg/person/
day, and its equivalent dose in dogs was 6 μg/kg (converted
based on body surface area). Therefore, we performed
pharmacokinetic studies of BPC157 in beagle dogs
following single IV administration at a dose of 6 μg/kg,
single IM administration at doses of 6, 30, or 150 μg/kg,
and repeated IM administration at a dose of 30 μg/kg for
seven consecutive days. The administration of BPC157 was
well tolerated by all dogs, and no visual signs of toxicity were
observed, which was consistent with our previous safety
evaluation studies. No noticeable difference in the plasma
FIGURE 1
Pharmacokinetic studies of BPC157 in rats (mean ± SD, n=6).(A) Total plasma concentration versus time profiles of BPC157 following
intravenous administration at a dose of 20 μg/kg; (B) Total plasma concentration versus time profiles of BPC157 following intramuscular
administration at the doses of 20, 100, or 500 μg/kg; (C) Total plasma concentration versus time profiles of BPC157 following repeat intramuscular
administration at a dose of 100 μg/kg for seven consecutive days (red) or a single intramuscular administration at a dose of 100 μg/kg (blue). (D)
Linear regression between BPC157 AUC and doses evaluated following intramuscular administration of doses 20, 100, or 500 μg/kg. (E) Linear
regression between BPC157 C
max
and doses evaluated following intramuscular administration of doses 20, 100, or 500 μg/kg. The goodness of fit
was estimated by the coefficient of determination (r
2
). Data are representative of three independent experiments.
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He et al. 10.3389/fphar.2022.1026182
concentration of BPC157 was found between male and
female dogs.
The mean (+SD) BPC157 plasma concentration versus time
curves following administration of various BPC157 doses in dogs
are shown in Figures 2A–C, and the corresponding
pharmacokinetic parameters are presented in Tables 4–Tables
6. After single IV administration, the t
1/2
and AUC
0–t
of
BPC157 in dogs were 5.27 min and 76.4 ± 30.2 ng min/ml.
After single IM administration at doses of 6, 30, or 150 μg/kg,
the T
max
values of each dose were 6.33, 8.67, and 8.17 min,
respectively. The C
max
values of each dose were 1.05 ± 0.429,
3.30 ± 0.508, and 26.1 ± 7.82 ng/ml, respectively, and the AUC
0–t
values were 29.0 ± 2.68, 160 ± 21.0, and 830 ± 247 ng min/mL
respectively. Linear relationships were observed between AUC
0–t
and BPC157 doses, as well as between C
max
and BPC157 doses
(Figures 2D,E). The absolute bioavailability observed after IM
administration of each dose in dogs was 45.27%, 47.64%, and
50.56%, respectively. After repeated IM administration of
BPC157 at 30 μg/kg for seven consecutive days, the plasma
concentration versus time curve was similar to that observed
after a single IM injection of 30 μg/kg (Figure 2C). However, the
pharmacokinetic parameters after repeated IM administration
changed slightly compared to those observed after a single IM
injection, with a small decrease in C
max
and t
1/2
and an increase in
T
max
. The area under the curve (AUC) values did not change
significantly (Table 6). The aforementioned results showed that
BPC157 reached its peak rapidly in beagle dogs and was rapidly
eliminated after reaching its peak. The prototype drug could not
be detected 4 h after administration, and its elimination half-life
was less than 30 min. BPC157 showed linear pharmacokinetic
characteristics in beagle dogs at the experimental dose.
2.3 Excretion, metabolism, and tissue
distribution of BPC157
In the aforementioned studies, we characterized the
pharmacokinetic profile of prototype BPC157 using high-
performance liquid chromatography (HPLC) in rats and dogs.
Next, we evaluated the excretion, metabolism, and tissue
TABLE 1 Pharmacokinetic parameters of BPC157 in rats following a single intravenous administration (mean ± SD, n=6).
AUC
0–90min
AUC
0-∞
MRT t
1/2
V
ss
CL
(ng·min/ml) (ng·min/ml) (min) (min) (ml/kg) (ml/min/kg)
399 400 0.727 15.2 36.4 50.1
AUC
0–90min
, area under the concentration/time curve at last observation; AUC
0–∞
, area under the concentration/time curve from 0 h to infinity; t
1/2
, half-life; V
ss
, volume of distribution
(steady state); CL, clearance.
TABLE 2 Pharmacokinetic parameters of BPC157 in rats following intramuscular administrations of doses ranging between 5 and 120 μg/kg (mean ±
SD, n=6).
Dosage T
max
C
max
AUC
0–t
AUC
0–∞
MRT t
1/2
F
a
(μg/kg) (min) (ng/ml) (ng·min/ml) (ng·min/ml) (min) (min) (%)
20 3.00 12.3 75.1 75.3 7.27 7.87 18.82
100 3.00 48.9 289 290 9.61 17.1 14.49
500 3.00 141 1930 1931 12.8 29.7 19.35
T
max
, time to peak concentration of drug in plasma; C
max
, peak concentration of drug in plasma; F
a
= (AUC
0–t
IM·DoseIV)/(AUC
0–t
IV·DoseIM) × 100%.
TABLE 3 Pharmacokinetic parameters of BPC157 in rats following repeat intramuscular administration of 100 μg/kg BPC157 for seven consecutive
days (mean ± SD, n=6).
T
max
C
max
AUC
0–t
AUC
0–∞
t
1/2
C
ssav
C
ssmin
(min) (ng/ml) (ng·min/ml) (ng·min/ml) (min) (ng/ml) (ng/ml)
3.00 60.4 418 419 18.5 0.290 0
C
ssav
= AUC
0–t
/τ,τis the interval of administration;C
ssmin
=(C
-48h
+C
-24h
+C
0h
)/3.
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He et al. 10.3389/fphar.2022.1026182
distribution of BPC157 in rats after a single IM injection of
100 μg/300 μCi/kg [
3
H]BPC157. [
3
H]BPC157 was well tolerated
by all rats, and no visual signs of toxicity were observed. Prolines
of BPC157 were labeled with [
3
H] and the structure of [
3
H]-
labeled BPC157 is shown in Figure 3A.
2.3.1 BPC157 excretion in rats evaluated by
examination of total radioactivity
The average recovery rates of total radioactivity in urine,
feces, and cage cleaning fluid collected from 0 to 72 h after [
3
H]
BPC157 administration in intact rats were 15.88% ± 2.99%,
FIGURE 2
Pharmacokinetic studies of BPC157 in beagle dogs (mean ± SD, n=6).(A) Total plasma concentration versus time profiles of BPC157 following
intravenous administration at a dose of 6 μg/kg; (B) Total plasma concentration versus time profiles of BPC157 following intramuscular
administration of doses 6, 30, or 150 μg/kg; (C) Total plasma concentration versus time profiles of BPC157 following repeated intramuscular
administration at a dose of 30 μg/kg for seven consecutive days (red) or a single intramuscular administration at a dose of 30 μg/kg (blue). (D)
Linear regression analysis between BPC157 AUC and doses following intramuscular administration of doses 6, 30, or 150 μg/kg. (E) Linear regression
analysis between BPC157 C
max
and doses following intramuscular administration of doses 6, 30, or 150 μg/kg. The goodness of fit was estimated by
coefficients of determination (r
2
). Data are representative of three independent experiments.
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He et al. 10.3389/fphar.2022.1026182
2.25% ± 0.67%, and 1.41% ± 1.04%, respectively, and the
proportion of residual radioactivity in the cadavers was
54.31% ± 3.04% (Table 7;Figure 3B). Furthermore, in bile
duct‒cannulated (BDC) rats, the average recovery rates of
total radioactivity in bile, urine, feces, and cage cleaning fluid
collected during 72 h after dosing were 9.08% ± 0.86%, 17.77% ±
6.35%, 2.73% ± 0.40%, and 0.91% ± 0.13%, respectively (Table 8;
Figure 3C). These results suggest that urinary excretion is the
dominant route of elimination following IM administration of
BPC157.
2.3.2 Plasma pharmacokinetic parameters of
BPC157 in rats evaluated based on total
radioactivity
After a single IM injection of 100 μg/300 μCi/kg [3H]
BPC157 in jugular vein‒cannulated (JVC) rats, the total
radioactivity concentrations in the whole blood and plasma
were similar between males and females. The total
radioactivity concentration versus time curve is shown in
Figure 3D. The corresponding pharmacokinetic parameters
are listed as follows: T
max
= 0.167 h, C
max
= 155 ± 11.8 ng
Eq./ml, AUC
0–t
= 4945 ± 417 h ng Eq./ml, AUC
0–∞
= 12956 ±
2074 h•ng Eq./ml, average residence time (MRT
0-t
) of plasma
total radioactivity = 33.2 ± 1.03 h, and t
1/2
= 102 h (Table 9).
Compared with the results of prototype BPC157 in rats, the
pharmacokinetic parameters of [
3
H]BPC157 evaluated based on
total radioactivity changed markedly, indicating the significant
metabolism and decomposition process of BPC157 in vivo.
2.3.3 Metabolite analysis of BPC157
We analyzed the metabolites of [
3
H]BPC157 in rat plasma,
bile, urine, and feces using the samples collected during the
aforementioned extraction and plasma pharmacokinetic studies.
First, using HPLC and HPLC-associated radioactive detector, we
identified six radioactive components, in addition to prototype
[
3
H]BPC157, in rat plasma collected at 0.05, 0.167, 1, 8, and 24 h
after administration (Supplementary Figure S1). Through high-
performance liquid chromatography-tandem mass spectrometry
(LC-MS/MS)-based molecular weight identification, standard
molecular weight comparison, and characteristic HPLC
profiles of the [
3
H]proline and [
3
H]BPC157 standards
(Supplementary Figure S2), we speculated the structures of
these six components and designated them as M1–M6
(Table 10). M1 was identified as [
3
H]proline and
TABLE 4 Pharmacokinetic parameters of BPC157 in dogs following a single intravenous administration (mean ± SD, n=6).
AUC
0–tmin
AUC
0-∞
MRT t
1/2
V
ss
CL
(ng·min/ml) (ng·min/ml) (min) (min) (ml/kg) (ml/min/kg)
76.4 ± 30.2 76.9 ± 30.2 2.49 ± 0.822 5.27 ± 2.25 243 ± 162 90.8 ± 40.1
AUC
0–90min
, area under the concentration/time curve at last observation; AUC
0–∞
, area under the concentration/time curve from 0 h to infinity; t
1/2
, half-life; V
ss
, volume of distribution
(steady state); CL, clearance.
TABLE 5 Pharmacokinetic parameters of BPC157 in dogs following intramuscular administration of doses ranging between 6 and 150 μg/kg (mean ±
SD, n=6).
Dosage (μg/kg) T
max
C
max
AUC
0-t
AUC
0-∞
MRT t
1/2
F
a
(min) (ng/ml) (ng·min/ml) (ng·min/ml) (min) (min) (%)
6 6.33 ± 3.14 1.05 ± 0.429 29.0 ± 2.68 30.0 ± 3.11 25.8 ± 7.35 20.0 ± 5.53 45.27 ± 24.85
30 8.67 ± 5.54 3.30 ± 0.508 160 ± 21.0 164 ± 21.5 37.0 ± 7.77 25.5 ± 7.08 47.64 ± 18.09
150 8.17 ± 2.99 26.1 ± 7.82 830 ± 247 831 ± 246 31.4 ± 15.2 29.3 ± 5.06 50.56 ± 27.01
T
max
, time to peak concentration of drug in plasma; C
max
, peak concentration of drug in plasma; F
a
= (AUC
0–t
IM·DoseIV)/(AUC
0–t
IV·DoseIM) × 100%.
TABLE 6 Pharmacokinetic parameters of BPC157 in dogs following repeated intramuscular administration at a dose of 30 μg/kg for seven
consecutive days (mean ± SD, n=6).
T
max
(min) C
max
(ng/ml) AUC
0–t
(ng·min/ml) AUC
0-∞
(ng·min/ml) t
1/2
(min) C
ssav
(ng/ml) C
ssmin
(ng/ml)
10.5 ± 10.5 5.89 ± 2.41 155 ± 25.2 158 ± 26.0 19.6 ± 3.72 0.108 ± 0.0177 0.00285 ± 0.00698
C
ssav
= AUC
0–t
/τ,τis the interval of administration; C
ssmin
=(C
-48h
+C
-24h
+C
0h
)/3.
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He et al. 10.3389/fphar.2022.1026182
FIGURE 3
Evaluation of BPC157 excretion in rats by examination of total radioactivity. (A) The structure of [
3
H]-labeled BPC157. [
3
H]-labeled sites are
indicated by T (red). (B) The average recovery of total radioactivity in the urine, feces, cage cleaning fluid, and cadavers during 0–72 h after [
3
H]
BPC157 administration in intact rats (mean ± SD, n=6).(C) The average recovery of total radioactivity in the urine, feces, and cage cleaning fluid
collected during 0–72 h after [
3
H]BPC157 administration in bile duct cannulated rats (mean ± SD, n=6).(D) Total radioactivity concentration
versus time curve for [
3
H]BPC157 in jugular vein cannulated rats following a single intramuscular injection at a dose of 100 μg/300 μCi/kg (mean ±
SD, n= 6). Data are representative of three independent experiments.
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M2–M6 were identified as a variety of small molecular peptides
generated upon the degradation of [3H]BPC157. Based on the
structures of the M1–M6 metabolites, we proposed the metabolic
process of BPC157 in vivo (Figure 4). The proportions of
M1–M6 and [
3
H]BPC157 in plasma radioactive components
at different sampling times demonstrated that [
3
H]
BPC157 was the main plasma component at 0.05 h (3 min)
after administration and was subsequently degraded into small
molecular peptide fragments in the following 0.167 h (10 min)
(Figure 5A). At 1 h after administration, [
3
H]proline accounted
for 86.65% of the plasma radioactive components. Subsequently,
the proportion of tritium water increased and that of [
3
H]proline
decreased gradually with time.
Next, we analyzed the main metabolites of [
3
H]BPC157 in
urine collected from 0 to 8 h and from 8 to 72 h and in bile and
feces collected from 0 to 72 h after administration. No new
metabolites were found in urine, bile, and fecal samples other
than the six components found in the plasma. In the mixed urine
samples collected from 0 to 8 h, the content of [
3
H]proline (M1),
the main metabolite, was higher, accounting for 13.9% (female)
and 11.7% (male) of the total radioactivity. In mixed urine
samples collected between 8 and 72 h, the proportion of
tritium water was higher, accounting for 69.5% (female) and
75.3% (male) of the total radioactivity, and [
3
H]proline (M1)
accounted for 3.11% (female) and 4.17% (male) of the total
radioactivity (Figure 5B). The total radioactivity excretion in
mixed bile samples collected between 0 and 72 h was low, and
tritium water was primarily detected, accounting for 91.2%
(females) and 91.0% (males) of the sample. The main
metabolite, [
3
H]proline (M1), accounted for 4.96% (female)
and 3.93% (male) of the bile samples (Figure 5C). Small
amounts of [
3
H]BPC157 were detected in feces, accounting for
0.63% (female) and 2.26% (male) of the total fecal radioactivity.
The tritium water content was 30.1% (female) and 29.3% (male),
and the content of [
3
H]proline (M1) was higher, accounting for
20.7% (female) and 30.2% (male) of the total radioactivity
TABLE 7 The recovery of total radioactivity in the urine, feces, and cage cleaning fluid during 0–72 h after intramuscular administrat ion of [3H]
BPC157 in rats.
Time interval (hour) Recovery of radioactivity (%)
Urine Feces Cage cleaning fluid Cadavers
0–8 9.11 ± 2.21 —— —
0–24 11.25 ± 2.54 1.31 ± 0.54 0.94 ± 0.91 —
0–48 13.84 ± 3.00 1.92 ± 0.61 1.08 ± 0.93 —
0–72 15.88 ± 2.99 2.25 ± 0.67 1.41 ± 1.04 54.31 ± 2.27
TABLE 8 The recovery of total radioactivity in bile, urine, feces, and cage cleaning fluid during 0–72 h after intramuscular administration of [3H]
BPC157 in BDC rats.
Time interval (hour) Recovery of radioactivity (%)
Bile Urine Feces Cage cleaning fluid
0–8 1.61 ± 0.55 6.37 ± 0.54 ——
0–24 3.86 ± 1.18 10.62 ± 4.10 0.92 ± 0.34 0.29 ± 0.08
0–48 6.92 ± 1.55 13.53 ± 5.11 1.84 ± 0.33 0.59 ± 0.17
0–72 9.08 ± 0.86 17.77 ± 6.35 2.73 ± 0.40 0.91 ± 0.13
TABLE 9 Plasma pharmacokinetic parameters examined based on total radioactivity following a single intramuscular administration of 100 μg/
300 μCi/kg of [3H]BPC157 in rats (mean ± SD, n=6).
T
max
(h) C
max
(ng-Eq./ml) AUC
0–t
(ng-Eq./ml) AUC
0–∞
(h·ng·min/ml) t
1/2
(h) MRT
0–t
(h)
0.167 155 ± 11.8 4945 ± 417 12956 ± 2074 102 ± 32 33.2 ± 1.03
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TABLE 10 Structures of six metabolites identified by high-performance liquid chromatography-tandem mass spectrometry in rat plasma, bile, urine,
and feces following a single intramuscular administration of 100 μg/300 μCi/kg of [3H]BPC157.
Designation Structure Molecular weight (Da) Retention time (min)
BPC157 1419.5 ~39.8
M1(Proline) 115.1 ~5.1
M2 1207.3 ~19.5
M3 1150.2 ~19.4
M4 1021.1 ~19.1
M5 1079.1 ~18.7
(Continued on following page)
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He et al. 10.3389/fphar.2022.1026182
(Figure 5D). The contents of other metabolites in feces were all
lower than 0.06% of the administered amount, and it was
impossible to perform structural identification because of the
extremely low content. These results suggest that BPC157 was
rapidly metabolized into low levels of a variety of small peptide
fragments, finally resulting in a single amino acid represented by
[
3
H]proline, which entered the normal amino acid metabolism
and excretion pathway in the body.
2.3.4 Tissue distribution of BPC157 in rats
The total radioactivity concentrations in the rat tissues were
similar after a single IM injection of 100 μg/300 μCi/kg of [3H]
BPC157. Tissue distributions at different time points are
summarized in Figure 6. After 3 min of administration, total
radioactivity concentration was detected in all rat tissues;
however, it was significantly lower than that observed in the
plasma. After 10 min of administration, the total radioactivity
concentration increased significantly in all tissues, with the mean
renal tissue concentration reaching 223 ng (Eq. μg/ml), which
was higher than the mean plasma concentration (150 ng, Eq./ml).
After 1 h of administration, the total radioactivity peaked in most
tissues, and the average concentration in the kidney was the
highest, reaching 560 ng (Eq. μg/ml), followed by that in the liver,
stomach wall, spleen, and thymus. All average concentrations
were higher than those in the plasma. The total radioactivity
concentrations in the intestine, skin, and lungs were similar to
those in the plasma, and the mean concentrations in the gonads,
myocardium, skeletal muscle, brain, and body fat were all lower
than the mean concentrations in the plasma. At 24 h after
administration, the mean concentrations of total radioactivity
in the kidney, thymus, liver, spleen, and gastric wall decreased
significantly but were still higher than the mean concentrations
in the plasma at the same time. The concentrations in other
tissues were lower than the average concentration in the plasma
and are presented in the descending order as follows: intestinal
tract, lung, gonad, skin, skeletal muscle, cardiac muscle, whole
blood, brain, and body fat. The total radioactivity concentrations
in the kidney, liver, stomach wall, thymus, spleen, intestine, lung,
skin, and body fat were reduced by approximately 50% compared
with the peak concentration in the same tissue (1 h after
administration).
3 Discussion
Pharmacokinetic evaluations are necessary and vital for the
development of new drugs. To translate BPC157 into the clinic,
we previously conducted preclinical safety studies and found that
BPC157 was well tolerated and did not demonstrate serious
toxicity (Xu et al., 2020). This study aimed to investigate the
pharmacokinetics of BPC157. Experiments were performed to
characterize the pharmacokinetics, absorption, distribution,
metabolism, and excretion characteristics of BPC157 in rats
and dogs.
We studied the pharmacokinetics of BPC157 after its IV
and IM administration in rats and beagle dogs. According to
the results, the elimination half-life (t
1/2
)oftheprototype
BPC157waslessthan30min,andBPC157showedlinear
pharmacokinetic characteristics in rats and beagles at all
experimental doses. After IM injections of 20, 100, and
500 μg/kg of BPC157 in rats and 6, 30, and 150 μg/kg of
BPC157 in beagles, plasma BPC157 reached its peak rapidly
(within 9 min). The pharmacokinetic parameters of
BPC157 did not significantly change after repeated
administration of BPC157 compared to those observed
after a single IM injection of the same dose administered
daily for 7 days. The mean absolute bioavailability observed
after IM injections was approximately 14%–19% in rats and
45%–51% in beagle dogs. In contrast to small-molecule
compounds, peptide drugs demonstrate pharmacokinetic
characteristics of short elimination half-life and poor
metabolic stability in vivo.Generally,t
1/2
values of peptide
TABLE 10 (Continued) Structures of six metabolites identified by high-performance liquid chromatography-tandem mass spectrometry in rat plasma,
bile, urine, and feces following a single intramuscular administration of 100 μg/300 μCi/kg of [3H]BPC157.
Designation Structure Molecular weight (Da) Retention time (min)
M6 777.9 ~19.0
Rt, Retention time on LC-MS/MS.
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He et al. 10.3389/fphar.2022.1026182
FIGURE 4
Speculated metabolic pathways of BPC157 in vivo. BPC157 gradually degraded into small molecular fragments and finally into single amino
acids, which entered the metabolic circulation in vivo.
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He et al. 10.3389/fphar.2022.1026182
drugsrangefromafewminutestoanhour(Wang et al., 2016).
The presence of a large number of proteolytic enzymes and
peptidases in the body is the primary reasons for this
phenomenon (Sharma et al., 2013). Therefore, in terms of
the elimination half-life, BPC157 conformed to the
characteristics of general peptide drugs. Our previous work
has shown that IM injection of prototype BPC157 can
effectively promote wound healing, and we aim to conduct
clinical trials examining BPC157 for the treatment of severe
trauma and burns in China. Nevertheless, extending the half-
life of BPC157 and further improving its pharmacokinetic
characteristics are important directions for the future
development of this drug.
The radioisotope probe assay is a cost-effective and fast
method for generating informative data for early preclinical/
pharmacokinetic absorption, digestion, metabolism, and
excretion studies of biotherapeutics (Roffey et al., 2007;Khalil
et al., 2011;Chen et al., 2014). We labeled the proline of
BPC157 with tritium and then studied the metabolism,
excretion, and tissue distribution characteristics of BPC157 by
examining the total radioactivity. The results of the excretion
experiment showed that the main excretory pathways of
BPC157 involve the liver and kidney, which was also
consistent with the excretion characteristics of peptide drugs
(Czock et al., 2012;Li et al., 2015). The tissue distribution results
showed that the radioactivity intensity in most tissues peaked 1 h
FIGURE 5
Changes in the proportion of six metabolites (M1‒M6) with time in plasma (A), urine (B), bile (C), and feces (D) after a single intramuscular
administration of 100 μg/300 μCi/kg of [3H]BPC157 in rats (mean ± SD, n= 6). Data are representative of three independent experiments.
Frontiers in Pharmacology frontiersin.org12
He et al. 10.3389/fphar.2022.1026182
after administration, which was slightly later than the peak time
of the total radioactivity concentration in plasma (0.167 h). The
peak concentrations of radioactivity in the kidney, liver, stomach
wall, thymus, and spleen were significantly higher than those in
the plasma. The concentrations in the intestinal tract, lungs, and
skin were similar to those in the plasma, followed by those in the
gonads, cardiac muscle, skeletal muscle, and whole blood. The
concentrations were lowest in the brain and body fat. These
results suggested that BPC157 can enter tissues and cells to
perform biological functions.
Determination of metabolites was the most challenging
aspect of this study. The metabolism of peptides and
proteins usually starts from the action of endopeptidase and
then undergoes multi-step enzymatic degradation to produce
the final metabolite amino acids, which enter the amino acid
pool in vivo (Vugmeyster et al., 2012). In rat plasma, we
identified six radioactive components, in addition to the
prototype [
3
H]BPC157, and their structures were predicted
by LC-MS/MS molecular weight identification and
comparison with standards. Through the analysis of possible
hydrolysis sites, we predicted the metabolic process of
BPC157 and proved that BPC157 was finally metabolized
into a single amino acid, represented by [
3
H]proline, in
plasma, urine, and feces. These results show that
BPC157 conforms to the metabolic process of peptide drugs,
further proving its metabolic safety. However, analysis of the
proportions of various metabolites in plasma over time once
again suggested a short half-life and rapid degradation of
prototype BPC157. In addition, we did not conduct
metabolite analysis in tissues, especially in target organs,
owing to the small sample size. The analysis of metabolites
in tissues is important for further pharmacodynamic
examination of BPC157 and explanation of its efficacy.
In conclusion, the present study is the first systematic report
evaluating the pharmacokinetics, tissue distribution, metabolism,
and excretion of BPC157. Many methodological validations were
not included because of the limited space of the article. The
results showed that the pharmacokinetic characteristics of
BPC15 were consistent with the general properties of peptide
drugs. In the future, we will conduct clinical trials for examining
BPC157 for the treatment of severe trauma and burns. The
observations of the present study and previous safety
evaluation and pharmacodynamic research will provide basic
information for further comprehensive clinical research. This
study also provides a reference for the development of various
peptide drugs.
4 Materials and methods
4.1 Test article and materials
BPC157 was synthesized and purified via HPLC in our
laboratory with 99% purity. This compound was sterilized and
lyophilized to meet the regulatory requirements of preclinical
studies. [3H]BPC157 was synthesized by Moravek Biochemicals
Inc. The specific radioactivity was 71.7 Ci/mmol, the radioactive
purity was 99.6%, and the total amount was approximately
10 McUrie. The tritium labeling sites were located on two
prolines.
BPC157 solution for administration was prepared by diluting
the required amount of concentrated BPC157 solution in 0.9%
NaCl injection solution prior to administration. The clinical dose
of 200 μg/person/day of BPC157 was converted to 20 μg/kg for
rats and 6 μg/kg for dogs. Based on its conversion according to
body surface area and detection sensitivity, 100 μg/300 μCi/kg
[3H]BPC157 was used for tritium labeling experiment in rats, 20,
100, and 500 μg/kg of BPC157 was used for unlabeled experiment
in rats, and 6, 30, and 150 μg/kg of BPC157 was used for
unlabeled experiment in dogs.
FIGURE 6
Tissue and organ distribution of [
3
H]BPC157 after a single intramuscular administration of 100 μg/300 μCi/kg of [
3
H]BPC157 in rats (mean ± SD
n= 6 per time point), expressed as the content of BPC157 per gram of tissue/organ. Data are representative of three independent experiments.
Frontiers in Pharmacology frontiersin.org13
He et al. 10.3389/fphar.2022.1026182
Warfarin sodium was purchased from Tokyo Chemical
Industry Co. Ltd., Lot: 340JE. Heparin sodium and normal
saline were obtained from Sinopharm Chemical Reagents Co.
Ltd. (Shanghai, China). 3H scintillation solution was purchased
from R.J. Harvey Co. (Tappan, NY). Ultima Gold scintillation
solution was purchased from Perkin Elmer (Waltham, MA,
United States). HPLC-grade acetonitrile, formic acid, and
methanol were obtained from Merck (Darmstadt, Germany).
HPLC-grade water was produced using a Milli-Q
®
ultrapure
water purification system (Bedford, MA, United States).
4.2 Animals
Approximately six-week-old SD rats weighing approximately
220 g were purchased from Beijing Vital River Laboratory
Animal Technology Co., Ltd. The rats were maintained in an
animal room with an air-conditioned barrier system at an
ambient temperature of 25°C±2
°C, relative humidity of
50% ± 10%, and a 12 h light/dark cycle. Ten-to-twelve-
month-old beagle dogs weighing between 9.8 and 12.8 kg were
purchased from YaDong Experimental Animal Research Centre,
Nanjing, China. The dogs were raised in an open feeding farm
under conditions involving natural light. The animals were
provided with ad libitum access to clean drinking water and a
standard pellet diet. The dogs were acclimatized to the housing
conditions for at least 7 days prior to the initiation of the
experiment. All animals were treated humanely, and all
studies were carried out in accordance with good laboratory
practice (GLP) (China Food and Drug Administration, CFDA)
guidelines for nonclinical laboratory studies of drugs issued by
the National Scientific and Technological Committee of the
People’s Republic of China. Animal care and welfare were
performed in accordance with the Guide for the Care and Use
of Laboratory Animals.
4.3 Pharmacokinetic parameters in
Sprague-Dawley rats after intravenous
and intramuscular administration
A total of 324 SD rats were randomly divided into five
groups, including 66 rats in group one, 60 rats each in groups
two to four, and 78 rats in group five, with each group comprising
half male and half female subjects. Group one was administered
20 μg/kg BPC157 saline solution intravenously. Groups two,
three, and four were administered 20, 100, and 500 μg/kg
BPC157 saline solutions via single IM injections, respectively.
Group five was administered 100 μg/kg BPC157 normal saline
solution by IM injection once a day for seven consecutive days.
Blood samples were collected from rats in groups one to four at
the corresponding time points before (0 h) and within 6 h after
BPC157 administration. Blood samples were collected from rats
in group five before the last three doses and within 6 h after the
last dose. Three male and three female rats were selected at each
time point, and approximately 7 ml of whole blood was collected
by heart puncture. Blood was centrifuged at 4°C to obtain plasma
and stored at 20°C until further analysis. The concentration of
BPC157 in the animal plasma at different time points was
determined by high-performance liquid chromatography-
tandem mass spectrometry (LC-MS/MS). The calibration and
quality control samples of BPC157 were prepared using animal
plasma with K3EDTA as anticoagulant, and dextromethorphan
was used as the internal standard of BPC157. The analyte and
internal standard were extracted from 50 μl of plasma by solid
phase extraction. BPC157 and internal standard were separated
by reverse-phase chromatographic column, and the analyte was
quantified by electrospray ionization (ESI) on a tandem four-
stage mass spectrometer. The confirmed linear quantification
range of BPC157 was 4.00 and 4,000 ng/ml. The pharmacokinetic
parameters were calculated using the mean concentration and
Watson LIMS software according to the non-atrioventricular
model.
4.4 Pharmacokinetic parameters in beagle
dogs after intravenous and intramuscular
administration
Inthispartoftheexperiment,threemaleandthreefemale
beagles were examined for four cycles. In the first cycle, a
normal saline solution (6 μg/kg) of BPC157 was administered
intravenously. In the second and fourth cycles, the animals were
administered 6, 30, and 150 μg/kg BPC157 saline solutions via
single IM injections. In the third cycle, the dogs were
administered 30 μg/kg BPC157 saline solution by IM
injection once a day for seven consecutive days. Blood
samples were collected at the corresponding time points
before (0 h) and within 6 h of a single administration. Blood
samples were collected from dogs administered multiple doses
at corresponding time points before the first dosing (0 h),
within 6 h after dosing, before the last three doses, and at
corresponding time points after the last dosing.
Approximately 3 ml of whole blood was collected at each
time point through the venous plexus of the forelimb. The
plasma was stored at −20°C for analysis.
4.5 Pharmacokinetic, tissue distribution,
and excretion studies in rats administered
radioactive-labeled BPC157
Thirty intact SD rats, six JVC rats, and six BDC rats (half
male and half female subjects) were injected intramuscularly with
100 μg/300 μCi/kg of [3H]BPC157. Whole blood and plasma
samples of six JVC rats were collected at 0.05, 0.167, 0.5, 1, 2, 4, 8,
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He et al. 10.3389/fphar.2022.1026182
24, 48, and 72 h after administration (three males and three
females at each time point) for the examination of radio
pharmacokinetics of total plasma. Six intact SD rats were used
for urinary, fecal, and biliary excretion studies. Urine and fecal
samples were collected from each rat at 0–8, 8–24, 24–48, and
48–72 h. Animal carcasses were collected 72 h after
administration. Bile excretion was studied in six SD rats with
BDC. Bile, urine, and feces were collected 0–72 h after
administration. Tissue distribution of BPC was studied in
24 intact SD rats. The rats were euthanized, and tissue
samples (brain, heart, kidneys, liver, spleen, lung, stomach,
intestine, muscle, grease, ovaries, womb, testicles, and thymus)
were collected at 3 min, 10 min, 1 h, and 24 h after
administration (three males and three females at each time
point). Male SD rats were administered a single IM injection
of blank solvent (excipient), and biological samples, including
whole blood, plasma, urine, feces, and tissues, were collected for
background control. The radioactivity of the plasma, tissue, bile,
urinary, and fecal samples was analyzed using a liquid
scintillation counter.
4.6 Metabolism
Plasma, bile, urine, and fecal samples of intact SD rats or
BDC rats after a single administration of [3H]BPC157 were
analyzed by HPLC combined with a low-energy radionuclide
detection technique to obtain the radiometabolite profiles of [3H]
BPC157. The structures of the main metabolites of [3H]
BPC157 in rat plasma, bile, urine, and feces were analyzed
and identified using LC-MS/MS and standard molecular
weight comparison.
4.7 Statistical analysis
All data are expressed as mean ± standard deviation.
Pharmacokinetic parameters were evaluated using the
WinNonlin software (version 5.3) according to a non-
atrioventricular model. Linear regression was examined
between AUC values obtained after BPC157 IM
administration and BPC157 doses and between C
max
values
and BPC157 doses. The goodness of fit was estimated using
the coefficients of determination (r
2
).
Data availability statement
The original contributions presented in the study are
included in the article/Supplementary Material, further
inquiries can be directed to the corresponding authors.
Ethics statement
The animal study was reviewed and approved by the
Laboratory Animal Welfare and Ethics Committee of Fourth
Military Medical University.
Author contributions
Conceptualization, YZ, WL, and ML. Methodology, LH and
DF. Validation, HG, KZ, WZ, and SW. Formal analysis, CZ, ZL,
and QH. Investigation, LH and DF. Data curation, YG, and JG.
Writing original draft preparation, WL. Writing review and
editing, ML, WL, and YZ. Supervision, YZ. Project
administration, KZ;. Funding acquisition, WL, YYZ, and ML.
All the authors have read and agreed to the published version of
the manuscript.
Funding
This work was supported by grants from the National
Natural Science Foundation of China (NSFC Numbers
81672800, 81603009, 81673020, 81802632, and 82173830),
Natural Science Foundation of Shaanxi (2020JQ-445), and the
Key Research and Development Program of Shaanxi Province
(2021SF-207, 2021SF-223, and 2022ZDLSF05-19).
Conflict of interest
The authors declare that the research was conducted in the
absence of any commercial or financial relationships that could
be construed as a potential conflict of interest.
Publisher’s note
All claims expressed in this article are solely those of the
authors and do not necessarily represent those of their affiliated
organizations, or those of the publisher, the editors and the
reviewers. Any product that may be evaluated in this article, or
claim that may be made by its manufacturer, is not guaranteed or
endorsed by the publisher.
Supplementary material
The Supplementary Material for this article can be found
online at: https://www.frontiersin.org/articles/10.3389/fphar.
2022.1026182/full#supplementary-material
Frontiers in Pharmacology frontiersin.org15
He et al. 10.3389/fphar.2022.1026182
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... BPC 157, a stable gastric pentadecapeptide derived from the Body Protecting Compound in human gastric juice, was administered in accordance with previously established protocols. 31,62,63,[68][69][70] The peptide (sequence: GEPPPGKPADDAGLV; molecular weight 1419.54 g/mol) was obtained from Sigma-Aldrich (Taufkirchen, Germany) and synthesized at >95% purity, verified by high-performance liquid chromatography (HPLC). It is readily soluble in saline and aqueous solutions at physiological pH (7.0). ...
... Based on prior pharmacological reports, the intraperitoneal dose was set at 20 μg/kg, consistent with established experimental applications. 31,62,63,[68][69][70] ...
... Although revascularization restores limb perfusion, it paradoxically induces oxidative stress, inflammation, endothelial dysfunction, and apoptosis, leading to tissue damage. 10 70 Pharmacokinetic studies in rats and dogs have demonstrated systemic absorption and distribution across multiple tissues, with elimination primarily via urinary and biliary pathways, supporting its bioavailability and translational relevance. 70 Pharmacodynamically, BPC 157 appears to exert pleiotropic cytoprotective effects rather than acting through a single pathway. ...
Alperen Kutay Yıldırım
Hüseyin Demirtaş Abdullah Özer
Mustafa Arslan
Ischemia-reperfusion (I/R) injury remains a major complication in peripheral arterial disease, characterized by oxidative stress, inflammation, and apoptosis. Body Protection Compound-157 (BPC 157), a stable gastric pentadecapeptide, has demonstrated cytoprotective properties in multiple tissues. This study aimed to evaluate the protective effects of BPC 157 in a rat model of lower limb I/R injury. Twenty-four male Wistar albino rats were randomized into four groups (n = 6): SHAM, B (BPC 157 only), IR (I/R), and IRB (I/R + BPC 157). I/R was induced by abdominal aortic clamping for 45 min followed by 2 h of reperfusion. BPC 157 (20 μg/kg, intraperitoneal) was administered at the 45th minute of ischemia in B and IRB groups. Biochemical markers (MDA, SOD, TAS, TOS) were measured in serum. Gene expression of Il-6, Hif-1α, p53, Bcl-2, Bax, and Casp3 was assessed by qRT-PCR, while immunohistochemistry evaluated VEGF, eNOS, IL-6, and Caspase-3 expression. Histopathological changes were scored with hematoxylin-eosin and Masson's trichrome staining. I/R significantly increased MDA, TOS, p53, Bax, Casp3, Hif-1α, Il-6, and histopathological injury scores, while reducing SOD, TAS, and VEGF expression. Bcl-2 mRNA was not significantly reduced by I/R compared with SHAM; however, BPC 157 significantly increased Bcl-2 expression compared with IR. In the IRB group, BPC 157 reduced MDA and TOS, restored SOD and TAS, downregulated p53, Bax, and Casp3, reduced IL-6 and Caspase-3 immunoreactivity, and partially restored VEGF expression. Histological analysis confirmed improved muscle architecture and reduced collagen deposition in IRB compared with IR. BPC 157 appears to exert protective effects against skeletal muscle I/R injury by attenuating oxidative stress, modulating apoptosis, reducing inflammation, and supporting angiogenic activity. These findings suggest that BPC 157 may represent a potential therapeutic candidate for mitigating reperfusion injury; however, further studies with larger cohorts and dose-response evaluations are required to confirm these effects and establish clinical relevance.
... Gastric stability is the compound's most distinctive and well-documented property: BPC-157 survives exposure to gastric juice at pH 1-2 with pepsin, in contrast to the vast majority of therapeutic peptides [1,2]. Plasma stability is poor, with a confirmed half-life of less than 30 min in both preclinical species and the only available human study, driven by rapid renal filtration and proteolytic hydrolysis [10,21]. Intestinal stability and hepatic first-pass extraction remain entirely uncharacterised. ...
... Accordingly, standard peptide delivery approachesaqueous parenteral formulations, oral delivery with absorption enhancement, and local topical or intra-articular administration-are expected to be sufficient for biological activity, without the need for specialized cell-penetration technologies such as endosomal escape agents, fusogenic lipids, or CPP conjugation. This conclusion is consistent with the documented biological activity of BPC-157 following conventional intraperitoneal, intragastric, and subcutaneous administration in preclinical models [1,2,7,21], where no cell-penetration enhancement was employed. The absence of CPP character simplifies formulation strategy considerably relative to peptide therapeutics that must achieve intracellular delivery. ...
... Fourth, no study to date has characterized the relationship between plasma BPC-157 concentrations and observed biological effects-a fundamental requirement for PK/PD modeling and rational dose selection in clinical development [18]. While He and colleagues [21] employed an LC-MS/MS method for BPC-157 quantification in rat and dog plasma, this method has not been validated against FDA Bioanalytical Method Validation guidance for human matrices, and no published study has characterized BPC-157 concentrations in human plasma following therapeutic dosing with full analytical transparencyrepresenting a prerequisite gap that must be addressed before pharmacokinetic data acceptable to regulatory agencies can be generated. ...
Diana Mateescu Dragos-Mihai Gavrilescu Florin Eugen Constantinescu
Alexandra Enache
Background/Objectives: BPC-157 (body protection compound 157) is a synthetic pentadecapeptide derived from a gastric protein fragment with reported cytoprotective and regenerative properties across multiple organ systems. Despite over three decades of preclinical research demonstrating consistent biological activity, its pharmaceutical development remains rudimentary, with no approved formulation, no validated dosing regimen, and no completed Phase II clinical trial. This review critically evaluates BPC-157 from a biopharmaceutical and drug development perspective, examining its physicochemical and pharmacokinetic properties, formulation challenges across routes of administration, the pharmacokinetic–pharmacodynamic disconnect that characterizes its preclinical profile, and the regulatory and translational barriers that currently preclude clinical advancement. Methods: A narrative review of the literature was conducted using PubMed/MEDLINE, Embase, and Cochrane Library from database inception to April 2026. Search terms included “BPC-157”, “BPC157”, “body protection compound 157”, “pentadecapeptide”, and “GEPPPGKPADDAGLV”, each combined with “pharmacokinetics”, “formulation”, “biopharmaceutics”, “drug delivery”, “clinical trial”, “toxicology”, and “regulatory”. Patent databases (Espacenet, Google Patents) and regulatory agency websites (FDA, EMA, WADA) were searched independently. Searches were supplemented by forward and backward citation tracking of key references. Articles were selected based on relevance to biopharmaceutical characterization, pharmacokinetics, formulation science, clinical evidence, and regulatory status; pharmacodynamic studies were included insofar as they inform translational development. Evidence was synthesized with emphasis on pharmaceutical characterization, formulation science, and translational feasibility; no formal quality assessment instrument was applied, consistent with the narrative review design. Results: BPC-157 exhibits unusual stability in gastric juice and demonstrates activity via oral, parenteral, and topical routes, yet its human pharmacokinetic profile remains critically undercharacterized despite a recently published formal preclinical ADME study in two species confirming a sub-30-min plasma half-life, linear dose-proportional kinetics, and intramuscular bioavailability of 14–51% depending on species. A plasma half-life of under 30 min—confirmed preclinically and in a preliminary two-subject human pilot—contrasts with prolonged biological effects lasting hours to days—a disconnect with significant implications for dosing strategy and formulation design. No pharmaceutical-grade formulation has been developed or validated. The peptide lacks bcs classification data, permeability characterization, and formal excipient compatibility studies. Available clinical data derive from fewer than 30 subjects across three uncontrolled pilot studies, none of which employed standardized pharmaceutical preparations. Conclusions: BPC-157 presents a compelling but pharmaceutically underdeveloped profile. The primary barrier to clinical translation is not the absence of biological activity, but the absence of fundamental pharmaceutical science: characterized formulations, validated pharmacokinetics, and a coherent drug development strategy. Addressing these biopharmaceutical gaps is a prerequisite for any meaningful clinical program.
... The fully assembled peptide is subsequently cleaved from the resin for further purification and processing [19]. Purification techniques include high-performance liquid chromatography (HPLC) to eliminate incomplete chains or other unintended products, allowing for approximately 99% purity of BPC-157 [20]. ...
... Once fully prepared and purified, the peptide may be lyophilized into a powder form for storage and shipment, thereby preventing degradation prior to use [20]. Though such methods are intended to allow for easier maintenance and access for research purposes, they also facilitate illicit access to BPC-157, circumventing the need for extensive equipment and invasive procedures for administration. ...
... Though further studies are needed for full characterization, some initial reviews of the pharmacokinetic properties of BPC-157 reported linear characteristics with 14-19% bioavailability in rats and 45-51% in beagle dogs [20]. Based on a prototype BPC-157, the half-life of the biologic in animals appears to be less than 30 min [20]. ...
Claire Yuan Ariana Demers
Victor Silva Christopher L. Robinson
Body Protective Compound-157 (BPC-157) is a synthetic pentadecapeptide derived from gastric proteins that has demonstrated notable reparative and anti-inflammatory properties across diverse preclinical models. Experimental evidence reveals that BPC-157 supports angiogenesis, collagen synthesis, fibroblast activity, and modulation of nitric oxide pathways, contributing to enhanced healing of muscle, tendon, ligament, bone, and gastrointestinal tissue. Studies also report reduced inflammatory cytokine activity, improved microvascular integrity, and beneficial effects on pain modulation through peripheral and dopaminergic mechanisms. Although animal data indicate favorable safety and pharmacokinetics, human research remains limited to small pilot studies investigating musculoskeletal pain, interstitial cystitis, and intravenous administration, all suggesting potential therapeutic value without reported major adverse effects. However, inconsistent preparation standards, limited clinical validation, and regulatory restrictions underscore the need for rigorous controlled trials. BPC-157 remains a promising candidate for regenerative medicine, yet comprehensive evaluation is required before clinical translation can be recommended.
... VEGF2-NO pathway also promotes angiogenesis and fibroblast activity, while the FAK-paxillin pathway is responsible for fibroblast proliferation and collagen synthesis, making BPC-157 useful in musculoskeletal repairs and performance enhancement [84]. While BPC-157 is known to have a short half-life, often cited as less than 30 min, its effect in animal studies has been shown to persist for weeks to months [103][104][105][106]. These sustained effects are believed to be due to the activation of multiple gene expression pathways, as mentioned before, which can continue independently. ...
Woojin Lee Qing Zhao Ruan Jamal J. Hasoon Christopher L. Robinson
As the population ages, the incidence and prevalence of musculoskeletal degeneration, such as osteoarthritis, increase. While the currently accepted treatment options provide symptomatic and functional improvement, they do not halt the progression of osteoarthritis. This results in the eventual need for surgery for many patients with advanced osteoarthritis. Due to the seemingly inevitable progression of OA, many clinicians and researchers have shifted their focus to regenerative therapies. Orthobiologics, a specific type of regenerative therapy designed to treat orthopedic conditions, has been gaining traction in recent years due to the utilization of autologous biological substances and synthetic peptides in healing musculoskeletal injuries and degenerative conditions. Orthobiologics can be distinguished into one of four classes: cell-based, biologic fluids-based, matrix-based, molecular-based, and based on their composition. In this review, key examples of each class, mechanism of action, and current clinical data for each agent are examined. Limitations of current orthobiologics involve a lack of standardization in the preparation and administration of each agent, as well as uniformity in assessment endpoints across different clinical studies. Lastly, we will discuss future directions of orthobiologics as a therapy for the treatment of osteoarthritis. Keywords: knee osteoarthritis, orthobiologics, regenerative medicine, platelet-rich plasma
... These organ bath concentrations substantially exceed systemic plasma levels; pharmacokinetic data show that intramuscular injection of 100 μg/kg BPC 157 in rats yields peak plasma concentrations in the nanogram-per-milliliter range with a half-life under https://doi.org/10.3390/jcm15093488 30 min [66]. However, supraphysiological concentrations are standard in ex vivo organ bath pharmacology to characterize concentration-response relationships [67]. ...
Alperen Kutay Yıldırım Ahmet Onur Dastan
Meriç Demeli Ertuş
Bilge Pehlivanoglu
Background/Objectives: Body Protection Compound-157 (BPC 157) is a stable gastric pentadecapeptide with cytoprotective, pro-angiogenic, and nitric oxide (NO)-modulating properties that has gained increasing attention for its therapeutic potential. Although vasodilatory effects have been demonstrated in animal models, functional evidence in human arterial tissue remains limited. This study investigated the effects of BPC 157 on vascular tone in human internal mammary artery (IMA) rings and evaluated the contribution of endothelial NO signaling. Methods: Residual IMA segments obtained from elective coronary artery bypass graft surgeries (n = 12) were dissected into endothelium-intact and endothelium-denuded rings. Following equilibration, the rings were challenged by phenylephrine (PheE; 3 × 10−6 M) to induce contraction. Cumulative concentration–response curves of BPC 157 (0.01–1 mg/mL) for five consecutive doses were constructed. The involvement of NO was assessed by BPC 157 dose–response curves in the nitric oxide synthase (NOS) inhibitor Nω-nitro-L-arginine methyl ester (L-NAME; 10−6 M) pre-incubated rings. Maximum force of contraction, area under the curve, maximum response (Emax), and negative logarithm of the half-maximal effective concentration (pEC50) values were analyzed. Results: BPC 157 produced a concentration-dependent reduction in PheE-induced contraction in both groups, with significantly greater relaxation in endothelium-intact rings (p < 0.05). L-NAME increased contractile responsiveness in intact rings and attenuated BPC 157-induced relaxation. Under NOS inhibition, differences between groups progressively diminished and concentration–response curves converged at higher concentrations. Emax analysis demonstrated that endothelial integrity markedly enhanced maximal vasorelaxation, whereas this advantage was largely abolished after NOS inhibition. Conclusions: BPC 157 induces concentration-dependent vasorelaxation in human arterial tissue, predominantly mediated via an endothelium-dependent NO pathway. Endothelial integrity primarily enhances maximal efficacy, while residual effects indicate additional mechanisms. These findings provide early mechanistic evidence for the vascular activity of BPC 157, although further molecular and in vivo studies are required to clarify its clinical relevance.
... BPC-157 lacks FDA approval, is banned by the World Anti-Doping Agency for athletic use, and is widely available through unregulated online vendors, who market it as a "research chemical." This regulatory void generates multiple risks: absence of quality control standards permits contamination or dosage inconsistencies; lack of pharmacovigilance prevents adverse event monitoring; and the short detection window (less than 4 days), combined with primarily outof-competition use, facilitates doping in athletics [64,65]. While preclinical toxicity studies have not identified apparent adverse effects at high doses, the lack of comprehensive human safety data-particularly regarding long-term use, effects on growth signalling pathways, and potential carcinogenic risks-mandates caution [66]. ...
Madhan Jeyaraman
Naveen Jeyaraman Aadithya Siddarth Sridhar
Sathish Muthu
Peptides occupy a strategic position between small molecules and biologics, offering high target specificity, favourable safety profiles, and chemical tractability. In musculoskeletal medicine, they address diverse pathological processes—including inflammation, degeneration, infection, oncology, and fibrosis—through mechanisms that conventional therapeutics cannot replicate. Two principal frameworks underpin this field. Throughout this review, we differentiate bioactive peptides, defined as naturally occurring or food-derived sequences that exert physiological effects, from therapeutic peptides, which are purposefully engineered pharmaceutical agents intended for clinical application. Although conceptual and functional overlap exists, this distinction is important because the two categories are subject to different regulatory pathways and evidentiary requirements. Accordingly, peptides discussed in this review fall into two broad groups: first, bioactive peptides originating from food proteins, endogenous biological systems, or laboratory synthesis, typically comprising 2– 50 amino acids; and second, therapeutic peptides that are rationally designed to address traditional limitations of peptide-based agents, including proteolytic degradation and challenges related to stability, bioavailability, and delivery. This narrative review synthesizes perspectives from both bioactive and engineered peptide classes across musculoskeletal medicine. The narrative format was selected to accommodate heterogeneous evidence spanning preclinical mechanisms, clinical trials, and translational barriers where systematic synthesis would be inappropriate. The review maps engineering solutions to tissue-specific delivery challenges, critically appraises evidence across primary musculoskeletal indications, and identifies translational bottlenecks separating preclinical claims from clinical reality. The analysis integrates mechanistic plausibility, clinical trial data, and regulatory milestones to evaluate the maturity of peptide-based interventions. A recurrent pattern emerges: while mechanistic plausibility remains strong across peptide classes, clinical maturity varies significantly. Collagen peptides and glucagon-like peptide-1 (GLP-1) analogues demonstrate robust clinical translation, with regulatory approval validating their therapeutic relevance. In contrast, many regenerative and anti-infective peptide candidates remain predominantly in preclinical stages, despite compelling mechanistic data. This heterogeneity underscores the uneven trajectory of peptide therapeutics within musculoskeletal medicine. Peptides represent a promising molecular class with unique advantages over conventional therapeutics. However, the disparity between mechanistic promise and clinical maturity has direct implications for patient counselling, trial design, regulatory oversight, and ethical considerations surrounding the off-label and grey-market use of these therapies. Bridging this translational gap will require rigorous clinical validation, improved delivery strategies, and careful regulatory frameworks to ensure safe and effective integration of peptide therapeutics into musculoskeletal medicine.
Ivan Smoday
Vlasta Vuković Katarina Oroz
Anita Skrtic
Background. This rat study reveals a new point: the considerable impact of unilateral adrenalectomy, severe vascular and multiorgan failure, occlusion/occlusion-like syndrome, and the stable gastric pentadecapeptide BPC 157 therapy. Based on the recent Fourier transform infrared (FTIR) spectroscopy vascular disturbance studies, particularly those after unilateral adrenalectomy in rats, the noted cytoprotective vascular recovery effect of the BPC 157 therapy may be useful. Methods. In rats, unilateral adrenalectomy (at 15 min, 5 h, 24 h) leads to integrated gross and morphological changes, vascular alterations, oxidative stress parameters, molecular markers and occlusion/occlusion-like syndrome and BPC 157 as useful therapy (/kg ig) (10 μg, 10 ng). Results. Peripherally and centrally, counteraction includes the lesions (adrenal, brain, heart, lung, liver, kidney, gastrointestinal tract), organ hemorrhage, and thrombosis. Attenuated/eliminated were arrhythmias, intracranial (superior sagittal sinus), portal, caval hypertension, and aortic hypotension. Significant resolution occurred via activation of collateral pathways, the azygos vein (direct blood flow delivery), and the recovered peduncle of the inferior suprarenal artery and superior suprarenal vein. Virchow’s triad circumstances were reversed. Occlusion/occlusion-like syndrome was counteracted as a whole. Also, BPC 157 counteracted adrenal lesions (lipid depletion, congestion). There were higher cortisol values, but still very low, and a shift toward the left of the adrenal compensatory weight increase. For the indicative conclusion along with previous studies, mechanistically, BPC 157 therapy exhibits the NO-system modulation/oxidative stress balance, increases NO-level, counteracts oxidative stress (malondialdehyde (MDA)), upregulates NOS1–3, and VEGF-A expression. Conclusions. These effects of BPC 157 therapy and its easy applicability deserve further consideration.
Olaf Wojcieszuk Łukasz Starczewski Adrianna Babik
Kamil Bronikowski
Background: BPC-157 and GHK-Cu are synthetic peptides with potential in tissue repair, influencing molecular mechanisms in healing, angiogenesis and inflammation. Objective: This review synthesizes preclinical and clinical research on BPC-157 and GHK-Cu efficacy and safety in wound healing and tissue repair, examining mechanistic pathways and translational potential in clinical and sports medicine. Methods: Literature searches of PubMed, Embase and Cochrane Library included studies on wound healing, tissue regeneration, safety and clinical uses of BPC-157 and GHK-Cu without publication date restrictions. Results: Preclinical studies show BPC-157 promotes skin, tendon, muscle and bone healing via specific signaling pathways and growth factor upregulation. GHK-Cu enhances collagen/elastin synthesis, angiogenesis and fibroblast migration. Limited human trials evaluated BPC-157 for knee pain and IV safety, while GHK-Cu showed promise in skin quality trials. Both appear safe but lack comprehensive RCTs. Conclusion: BPC-157 and GHK-Cu show therapeutic potential in wound healing, though evidence is largely preclinical. Extensive human trials are needed to establish clinical efficacy. This review provides groundwork for future research and highlights safety for sports medicine practitioners.
Predrag Sikiric Ivan Barisic
Mario Udovicic
Anita Skrtic
This review presents an innovative and timely exploration of how cytoprotection can serve as a cohesive therapeutic approach by which to address the hemorrhage–thrombosis paradox. Presenting counteraction of both hemorrhage and thrombosis as phase-dependent outcomes of vascular dysregulation, the manuscript synthesizes conceptual, experimental, and clinical evidence into a unified systems-level model focused on the stable gastric pentadecapeptide BPC 157, which acts as a cytoprotective mediator. In rodents, BPC 157 can simultaneously counteract hemorrhage and thrombosis without directly affecting the coagulation cascade (aggregometry, thromboelastometry). This cytoprotective framework (decreased hemorrhage, decreased thrombosis) stands with presentation of both hemorrhage and thrombosis in the wound, arrhythmias, and Virchow triad, and resolution of these disturbances. As proof of the concept (full cytoprotective effect), a vasoprotective cytoprotective mediator capable of bidirectional regulation, BPC 157, is effective for wound healing, arrhythmia control, and normalization of Virchow’s triad (i.e., following major injuries, occlusion/occlusion-like syndromes). As a comparison from a cytoprotective (partial vs. full) standpoint, conventional agents—anticoagulants, antiplatelet drugs, and fibrinolytics—provide only partial protection by targeting isolated components of hemostasis. Beta blockers, calcium channel blockers, prostaglandins, NO modulators, ACE inhibitors, and statins each exert broader cytoprotective effects; however, these actions remain incomplete and context-dependent, typically unidirectional, dose-limited, or are achieved at the expense of opposing pathological risks. Contrarily, for BPC 157, decreased hemorrhage (including both anticoagulants and antiplatelet agents), decreased thrombosis, effective wound healing, arrhythmia control, and normalization of Virchow’s triad involve preservation of endothelial integrity, normalization of microcirculation, modulation of the NO system, stabilization of hemostatic balance, and recruitment of adaptive collateral pathways. Nevertheless, reliance on preclinical models necessitates further clinical validation.
Danijel Matek Irena Matek Mladen Japjec Mario Staresinic
As a novel theoretical and practical advantage, preclinical to clinical evidence, this systematic review of PRP, growth factors, and stable gastric pentadecapeptide BPC 157 efficacy in complex musculoskeletal and junctional injuries emphasizes the cytoprotection concept, healing to restore tissue integrity. Notably, the concept holds tendon, ligament, and muscle healing, in particular. Then, it holds their healing together as interconnected lesions. Consequently, this review presents the possibilities for cytoprotective therapies suited for tendon/ligament/muscle and recovery of osteotendinous, myotendinous, and the muscle-to-bone junction. The estimated key was the success of injury recovery amid each agent’s direct exogenous administration, alone or with a carrier, locally or systemically, without reliance on complex scaffolds, carriers, or tissue-engineering constructs. As reviewed, while with commonly acknowledged physiological significance, and acting throughout cytoprotection principles, growth factors (PDGF, TGF-β1, IGF-1, FGF, VEGF, BMPs) delivered locally with various carriers improve tendon, ligament, and muscle healing; however, some (PDGF, TGF-β1, IGF-1) may fail in muscle lesions, and all show limited or no efficacy in junctional healing. Contrarily, proposed as a cytoprotection mediator, BPC 157 acts alone with a full cytoprotection range, given systemically or locally. Moreover, without any carrier, BPC 157 acts alone, combining beneficial effects on tendon, ligament, and muscle injuries with osteotendinous, myotendinous, and muscle-to-bone healing. In rat studies, across systemic (intraperitoneal, intragastric, or drinking water) and local (cream) administration, BPC 157 consistently demonstrated efficacy, indicating considerable translational potential. Further clinical studies will strengthen cytoprotective therapy and, particularly, BPC 157 in complex musculoskeletal and junctional injuries.
Theresa Tze-kwan Lai Oi-Mei Yip Michael M. K. Sham
BACKGROUND: Pressure injury is a common clinical parameter of patient care outcome. Various risk factors increase the risk of palliative care patients to pressure injuries and difficult wound healing. Healthcare professionals are aware that wound healing is difficult, but they still focus on this process instead of providing the needs of patients with unhealed wounds. METHODS: This study aims to identify the clinical parameters of pressure injuries in relation to patients with advanced illness. A retrospective analysis of the records of patients with pressure injuries admitted over 18 months was performed. Descriptive analysis and Spearman's correlation coefficient were used. RESULTS: A total of 127 clinical records were reviewed. The study revealed that patients of old age, high creatinine level, advanced wound age, reduced palliative performance scale (PPS) and low Norton scores are prone to suffer from unhealed wounds. CONCLUSIONS: Pressure injuries are prone to non-healing in patients with old age, high creatinine level, advanced wound stage, low PPS and low Norton scores. Further studies involving patients in earlier stage can be considered.
Antonija Duzel
Josipa Vlainić Marko Antunovic
Predrag Sikiric
Aim: To provide new insights in treatment of colitis and ischemia and reperfusion in rats using stable gastric pentadecapeptide BPC 157. Methods: Medication [BPC 157, L-NAME, L-arginine (alone/combined), saline] was bath at the blood deprived colon segment. During reperfusion, medication was BPC 157 or saline. We recorded (USB microscope camera) vessel presentation through next 15 min of ischemic colitis (IC-rats) or reperfusion (removed ligations) (IC + RL-rats); oxidative stress as MDA (increased (IC- and IC + RL-rats)) and NO levels (decreased (IC-rats); increased (IC + RL-rats)) in colon tissue. IC + OB-rats [IC-rats had additional colon obstruction (OB)] for 3 d (IC + OB-rats), then received BPC 157 bath. Results: Commonly, in colon segment (25 mm, 2 ligations on left colic artery and vein, 3 arcade vessels within ligated segment), in IC-, IC + RL-, IC + OB-rats, BPC 157 (10 μg/kg) bath (1 mL/rat) increased vessel presentation, inside/outside arcade interconnections quickly reappeared, mucosal folds were preserved and the pale areas were small and markedly reduced. BPC 157 counteracted worsening effects induced by L-NAME (5 mg) and L-arginine (100 mg). MDA- and NO-levels were normal in BPC 157 treated IC-rats and IC + RL-rats. In addition, on day 10, BPC 157-treated IC + OB-rats presented almost completely spared mucosa with very small pale areas and no gross mucosal defects; the treated colon segment was of normal diameter, and only small adhesions were present. Conclusion: BPC 157 is a fundamental treatment that quickly restores blood supply to the ischemically injured area and rapidly activates collaterals. This effect involves the NO system.
Domagoj Drmic
Danijela Kolenc Spomenko Ilic
Predrag Sikiric
AIM To counteract/reveal celecoxib-induced toxicity and NO system involvement. METHODS Celecoxib (1 g/kg b.w. ip) was combined with therapy with stable gastric pentadecapeptide BPC 157 (known to inhibit these lesions, 10 μg/kg, 10 ng/kg, or 1 ng/kg ip) and L-arginine (100 mg/kg ip), as well as NOS blockade [N(G)-nitro-L-arginine methyl ester (L-NAME)] (5 mg/kg ip) given alone and/or combined immediately after celecoxib. Gastrointestinal, liver, and brain lesions and liver enzyme serum values in rats were assessed at 24 h and 48 h thereafter. RESULTS This high-dose celecoxib administration, as a result of NO system dysfunction, led to gastric, liver, and brain lesions and increased liver enzyme serum values. The L-NAME-induced aggravation of the lesions was notable for gastric lesions, while in liver and brain lesions the beneficial effect of L-arginine was blunted. L-arginine counteracted gastric, liver and brain lesions. These findings support the NO system mechanism(s), both NO system agonization (L-arginine) and NO system antagonization (L-NAME), that on the whole are behind all of these COX phenomena. An even more complete antagonization was identified with BPC 157 (at both 24 h and 48 h). A beneficial effect was evident on all the increasingly negative effects of celecoxib and L-NAME application and in all the BPC 157 groups (L-arginine + BPC 157; L-NAME + BPC 157; L-NAME + L-arginine + BPC 157). Thus, these findings demonstrated that BPC 157 may equally counteract both COX-2 inhibition (counteracting the noxious effects of celecoxib on all lesions) and additional NOS blockade (equally counteracting the noxious effects of celecoxib + L-NAME). CONCLUSION BPC 157 and L-arginine alleviate gastrointestinal, liver and brain lesions, redressing NSAIDs’ post-surgery application and NO system involvement.
Predrag Sikiric
Sven Seiwerth Rucman Rudolf
Josipa Vlainić
Background: Brain-gut interaction involves, among others, peptidergic growth factors which are native in GI tract and have strong antiulcer potency and thus could from periphery beneficially affect CNS-disorders. We focused on the stable gastric pentadecapeptide BPC 157, an antiulcer peptidergic agent, safe in inflammatory bowel disease trials and now in multiple sclerosis trial, native and stable in human gastric juice. Methods: Review of our research on BPC 157 in terms of brain-gut axis. Results: BPC 157 may serve as a novel mediator of Robert's cytoprotection, involved in maintaining of GI mucosa integrity, with no toxic effect. BPC 157 was successful in the therapy of GI tract, periodontitis, liver and pancreas lesions, and in the healing of various tissues and wounds. Stimulated Egr-1 gene, NAB2, FAK-paxillin and JAK-2 pathways are hitherto implicated. Initially corresponding beneficial central influence was seen when BPC 157 was given peripherally and a serotonin release in particular brain areas, mostly nigrostriatal, was changed. BPC 157 modulates serotonergic and dopaminergic systems, beneficially affects various behavioral disturbances that otherwise appeared due to specifically (over)stimulated/damaged neurotransmitters systems. Besides, BPC 157 has neuroprotective effects: protects somatosensory neurons; peripheral nerve regeneration appearent after transection; after traumatic brain injury counteracts the otherwise progressing course, in rat spinal cord compression with tail paralysis, axonal and neuronal necrosis, demyelination, cyst formation and rescues tail function in both short-terms and long-terms; after NSAIDs or insulin overdose or cuprizone encephalopathies were attenuated along with GI, liver and vascular injuries. Conclusion: BPC 157,a gastric peptide, may serve as remedy in various nervous system disorders.
Predrag Sikiric
Sven Seiwerth Rucman Rudolf
Josipa Vlainić
Background: Brain-gut interaction involves, among others, peptidergic growth factors which are native in GI tract and have strong antiulcer potency and thus could from periphery beneficially affect CNS-disorders. We focused on the stable gastric pentadecapeptide BPC 157, an antiulcer peptidergic agent, safe in inflammatory bowel disease trials and now in multiple sclerosis trial, native and stable in human gastric juice. Methods: Review of our research on BPC 157 in terms of brain-gut axis. Results: BPC 157 may serve as a novel mediator of Robert's cytoprotection, involved in maintaining of GI mucosa integrity, with no toxic effect. BPC 157 was successful in the therapy of GI tract, periodontitis, liver and pancreas lesions, and in the healing of various tissues and wounds. Stimulated Egr-1 gene, NAB2, FAK-paxillin and JAK-2 pathways are hitherto implicated. Initially corresponding beneficial central influence was seen when BPC 157 was given peripherally and a serotonin release in particular brain areas, mostly nigrostriatal, was changed. BPC 157 modulates serotonergic and dopaminergic systems, beneficially affects various behavioral disturbances that otherwise appeared due to specifically (over)stimulated/damaged neurotransmitters systems. Besides, BPC 157 has neuroprotective effects: protects somatosensory neurons; peripheral nerve regeneration appearent after transection; after traumatic brain injury counteracts the otherwise progressing course, in rat spinal cord compression with tail paralysis, axonal and neuronal necrosis, demyelination, cyst formation and rescues tail function in both short-terms and long-terms; after NSAIDs or insulin overdose or cuprizone encephalopathies were attenuated along with GI, liver and vascular injuries. Conclusion: BPC 157,a gastric peptide, may serve as remedy in various nervous system disorders.
Chuanyang Xu Lijuan Sun Fengling Ren
Weina li
BPC157 displays protective activity in various organs and tissues. This report presents preclinical toxicity studies with BPC157 in mice, rats, rabbits and dogs. The single-dose toxicity study did not show any test-related effects that could be attributed to the test article. In repeated-dose toxicity evaluations, BPC157 was well tolerated in dogs, with no abnormal changes between the BPC157-treated groups and the solvent control group, with the exception of a decrease in creatinine level at a dose of 2 mg/kg but not at lower doses. The animals recovered spontaneously after 2 weeks of withdrawal. This may be due to the pharmacological activity of BPC157. A local tolerance test showed that the irritation caused by BPC157 was mild. BPC157 also showed no genetic or embryo-fetal toxicity. In summary, BPC157 was well tolerated and did not cause any serious toxicity in mice, rats, rabbits and dogs. These preclinical safety data contribute to the initiation of an ongoing clinical study. Based on the stability and protective effect of BPC157, which has been widely reported, BPC157 may have a better application prospect than the widely used cytokine drugs in wound therapy.
Predrag Sikiric Rudolf Rucman Branko Turkovic
Sven Seiwerth
Years ago, we revealed a novel cytoprotective mediator, stable gastric pentadecapeptide BPC 157, particular anti-ulcer peptide that heals different organs lesions when given as a therapy, native in human gastric juice while maintaining GI- tract mucosal integrity, already tested in trials (ulcerative colitis and now multiple sclerosis). The stomach cytoprotection is the most fundamental concept, stomach cell protection and endothelium protection are largely elaborated, but so far cell, protection and endothelium protection outside of the stomach were not implemented in the therapy. However, having managed these two points, stomach cell protection and endothelium protection, either one or together, even much more than standard cytoprotective agents do, BPC 157 employed large scale of its beneficial effects seen in various organs. Providing endothelium protection, BPC 157 was shown to prevent formation and reverse established thrombosis in anastomosed abdominal aorta as well as venous thrombosis after inferior caval vein occlusion, and attenuate bleeding prolongation and thrombocytopenia after amputation, without or with anticoagulants, or venous occlusion, and finally counteract effect of L-NAME and/or L- arginine. Now, with BPC 157 application, we reveal the third most important part of the cytoprotection concept: with the stomach cell and endothelium protection to recover mucosal integrity, BPC 157 as prototype cytoprotective agent should also control blood vessel function, depending upon injury, perforated defect or vessel obstruction. After a perforated injury (i.e., stomach), BPC 157 therapy activates blood vessels "running" towards defect. After obstruction (i.e., inferior caval vein), BPC 157 activates vessels "running" towards bypassing defect, collaterals functioning. Reestablished blood flow, and largely reversed injurious course may practically implement the cytoprotection concept.
Ana Paula Lucas Mota
Cristiane Alves da Silva Menezes
Patrícia Alpoim
Luci Dusse
Aim: The maintenance of stable graft function in renal transplanted recipients (RTR) is a challenge for healthcare staff. The ideal biomarkers must have significative predictive values to monitor the intricate renal function response triggered after renal transplantation. The main purpose in this study was to evaluate the regulatory and pro-inflammatory cytokines as biomarkers of allograft function in living-related renal transplant patients. Methods: Regulatory and pro-inflammatory cytokine plasma levels were measured by flow cytometry in 120 living-related renal transplanted patients categorized into three groups according to creatinine plasma levels: creatinine less than 1.4 mg/dL (C1), creatinine within 1.4-2.0mg/dL (C2) and more than 2.0 mg/dL (C3). Patients were also classified as "low" or "high" cytokine producers. Clinical data were obtained from patients' medical record. Results: We have found a peak of regulatory cytokines in RTR with low creatinine levels as well as a peak of IL-6 pro-inflammatory cytokine in patients with high creatinine levels. C1 and C3 groups showed a mixed pro-inflammatory (IL-8, IL-6, IL-1β, TNF-α, IL-12 and IFN-γ) and regulatory (IL-4, IL-5 and IL-10) cytokine pattern and C2 had a predominant pro-inflammatory profile. C3 group showed a higher frequency of high pro-inflammatory cytokine producers compared to C1. Conclusion: Our data suggest that regulatory cytokines IL-4, IL-5 and IL-10 could be good biomarkers associated with stable renal function, while pro-inflammatory cytokines seems to be potential markers in RTR related to high creatinine plasma levels, specially IL-6 despite of its borderline values. Copyright © 2017 John Wiley & Sons, Ltd.
Ying Wang Aleksey Lomakin
Sonoko Kanai George B. Benedek
Hybrid incretin peptides are a new generation of drugs for the treatment of diabetes and obesity. Despite their biological potency, the effectiveness of these peptides as drugs is limited by their short circulation time in blood (typically within minutes). In this work, we show that lipid conjugated forms of a GLP-1/GIP/glucagon hybrid peptides stay in circulation for hours. We studied the oligomerization and albumin-binding of the unconjugated hybrid peptide as well as its lipidated variants. These lipidated peptides differ in the N-terminal mutation, the position of lipidation and the linkage to lipid. We found that these lipidated peptides form stable oligomers at concentrations above 1mg/mL. This concentration range is relevant to formulation and storage of the peptides. We observed no binding between the peptide oligomers and human serum albumin. However, at the expected therapeutic concentration range (~10-100ng/mL), the oligomers dissociate into monomers. The monomers of lipidated peptides bind to albumin. We have determined the dissociation constants of binding between the lipidated peptides and serum albumin. The dissociation constants of albumin-binding of our lipidated peptides are all very close and similar to that of the fatty acid binding of albumin. Our findings suggest that the monomeric lipidated peptides bind to HSA mainly by the fatty acid chain. Therefore, albumin binding is likely to be a universal mechanism of the prolonged circulating duration of lipidated pharmaceutical peptides.