Pharmacokinetics of small hyperbranched polyglycerols as an osmotic agent for peritoneal dialysis: Plasma exposure, organ distribution and excretion in rats

Abstract

Background: Small hyperbranched polyglycerol (HPG) has been recently of interest for peritoneal dialysis, but its pharmacokinetics is barely understood. This study investigated the absorption, distribution and excretion of 1 and 3 kDa HPG. Methods: Rats (naive, 5/6 nephrectomy (5/6 Nx) or bilateral nephrectomy (BNx)) received a single dose of 3H-labelled HPG-containing solutions intraperitoneally (IP) or intravenously (IV). Radioactivity in tissues, urine and faeces was counted using a scintillation counter. Pharmacokinetic parameters were calculated using WinNonlin software. Results: During 8-h dwell with IP injected therapeutic dose of HPG-based hypertonic solutions, the plasma levels of 1 kDa HPG reached the peak at 2 h, followed by a decrease to the end, whereas 3 kDa HPG increased for the duration of the 8 h. At the experimental endpoint, the distribution of both sizes of HPG in major organs was minimal, whereas most of 1 kDa HPG was excreted via urine, and of 3 kDa remained in peritoneal cavity. The elimination of both 1 and 3 kDa HPG after either IP or IV administration was significantly delayed by 5/6 Nx or BNx as compared to naive controls. Further, 24-h faecal excretion of HPG (3 kDa) was <5% of injected dose that was not different between healthy and BNx rats. Conclusion: Data suggest size-dependent peritoneal absorption of osmotic HPG that are not specifically absorbed by any of the organs tested. The clearance of small HPG mainly depends on kidney excretion, implying the risk of HPG accumulation in patients with end-stage kidney disease who receive maintenance dialysis with HPG.