Pharmacokinetics, distribution, metabolism, and excretion of body-protective compound 157, a potential drug for treating various wounds, in rats and dogs

Abstract

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 [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.

Keywords: BPC157; absorption; distribution; excretion; metabolism; pharmacokinetics; wounds.

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 (r²). Data are representative of three independent experiments.

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 (r²). Data are representative of three independent experiments.

FIGURE 3

Evaluation of BPC157 excretion in rats by examination of total radioactivity. (A) The structure of [³H]-labeled BPC157. [³H]-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 [³H]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 [³H]BPC157 administration in bile duct cannulated rats (mean ± SD, n = 6). (D) Total radioactivity concentration versus time curve for [³H]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.

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.

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.

FIGURE 6

Tissue and organ distribution of [³H]BPC157 after a single intramuscular administration of 100 µg/300 μCi/kg of [³H]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.