The pharmacokinetics of porcine C‐peptide after intraperitoneal injection

Abstract

Background Previously, we have demonstrated that there were very low C‐Peptide concentrations and normal blood glucose levels when we transplanted encapsulated islets in the abdominal cavity of diabetic nude mice. In addition, the C‐peptide concentration in the ascites fluid of the peritoneal cavity was 40 times higher than in the peripheral blood. In this study, we investigated the pharmacokinetics of intraperitoneal porcine C‐peptide. Methods To assess the pharmacokinetics of porcine C‐peptide, a synthesized porcine C‐peptide solution was injected into the peripheral circulation through the tail vein or into the peritoneal cavity in rats at low or high doses of either 200 or 2000 pmol/kg, respectively. Arterial blood samples were collected at time intervals of 1‐120 minutes after injection to calculate the terminal elimination half‐life (t1/2) and area under the time‐concentration curve (AUC0‐t). Results After intraperitoneal C‐peptide injection, the highest porcine C‐peptide concentration in peripheral blood was only one‐fortieth compared to after intravenous injection. The AUC0‐t for the intraperitoneal injection was 78% at the low dose and only 39% at the high dose compared to the intravenous injection. This finding indicates that C‐peptide remains in the abdominal cavity when intraperitoneally transplanted islets release C‐peptide via high glucose stimulation. Conclusions Porcine C‐peptide injected into a peritoneal cavity slowly and incompletely entered peripheral circulation, which resulted in very low concentration in peripheral blood.

Long‐term efficacy and safety of porcine islet macrobeads in nonimmunosuppressed diabetic cynomolgus macaques

“…Similar findings were also observed in our later studies of diabetic dogs implanted with porcine islet macrobeads 33 . Matsumoto's group has also reported a 40‐fold reduction in circulating porcine C‐peptide as compared to peritoneal fluid concentrations in diabetic mice implanted with encapsulated neonatal pig islets 59 and later demonstrated the incomplete entry of C‐peptide into the peripheral circulation after peritoneal injection 60 . Accordingly, the presence of detectable porcine C‐peptide in the peritoneal fluid is indicative of graft function.…”

“…33 Matsumoto's group has also reported a 40-fold reduction in circulating porcine C-peptide as compared to peritoneal fluid concentrations in diabetic mice implanted with encapsulated neonatal pig islets 59 and later demonstrated the incomplete entry of C-peptide into the peripheral circulation after peritoneal injection. 60 In another approach investigating the protective functions of C-peptide, even minimal residual C-peptide was reported to significantly reduce microvascular complications and the incidence of hypoglycemic episodes in 6000 people with type 1 diabetes followed for 5 years as part of the Scottish Diabetes Research Network. 68 These data are consistent with results of human islet allotransplantation that have reported reduced hypoglycemia, even in the absence of reductions of exogenous insulin or improvements in HbA1c levels.…”

Xenotransplantation literature update, July/August 2019

“…They concluded that under conditions of high glucose stimulation, intraperitoneally transplanted islets release C‐peptide. The C‐peptide initially stays within the abdominal cavity and is partially released into peripheral circulation in a very slow manner . This resulted in findings consistent with very low C‐peptide concentrations within the peripheral blood …”

“…In a separate study, after previously measuring serum levels of C‐peptide and glucose in the recipients of transplanted encapsulated islets in the abdominal cavity of diabetic nude mice, Iizuka et al performed a pharmacokinetic analysis of C‐peptide using a synthetic intraperitoneal porcine C‐peptide solution . They concluded that under conditions of high glucose stimulation, intraperitoneally transplanted islets release C‐peptide.…”

“…In the previous issue of Xenotransplantation, Zhou et al provided an updated review of the complement system in xenograft rejection; Hundrieser et al discuss how porcine and human MHC‐II polymorphisms influence donor reactivity; Ladowski et al seek to eliminate all donor xenoantigens; Cooper et al review a 9 gene alteration of porcine donors for clinical xenotransplantation; Zhou et al present a strategy to monitor xenograft rejection with porcine cDNA biomarkers; Zafar et al provide further research into reducing porcine islet immunoreactivity; Li et al studied the cold storage of porcine hepatocyte spheroids; Iizuka et al deep dive into porcine C‐peptide pharmacokinetics; and, finally, Zheng et al, Zhao et al, and Yoon et al provide updates in corneal xenotransplantation.…”