Toxicological and toxicokinetic analysis of angiotensin (1-7) in two species

Abstract

The objectives of this study were to determine the potential systemic and local toxicity, as well as evaluate the toxicokinetic (TK) profile of angiotensin (1-7) [A(1-7)] when administered daily via subcutaneous injection for 28 days to Sprague-Dawley rats and Beagle dogs. A(1-7) is a member of the renin-angiotensin system and has undergone clinical evaluation for the treatment of chemotherapy-induced myelosuppression. In this present study, A(1-7) was given at 10 mg/(kg day) for 28 days to rats and canines. At day 27, blood was harvested to evaluate the TK parameters. On day 28, systemic toxicology was evaluated. Following A(1-7) administration for 27 days, no plasma A(1-7) accumulation was detected in canines; however, increased A(1-7) plasma concentrations were detected in rats. Despite the accumulation observed in rats, no detectable toxicity was found following A(1-7) administration for 28 days. The TK analysis of A(1-7) revealed a plasma half-life of 20-30 min in both rats and canines. The time to maximum plasma concentration was found to be 15 and 26.25 min in rats and canines, respectively. This study shows that subcutaneous administration of A(1-7) at 10 mg/(kg day) for 28 days did not lead to any detectable toxicities in either rats or canines.

Figure 1

Time versus concentration curve of A(1–7) determined in canines, wherein the closed circles represent animals sampled on day 0 and the open squares represent animals that were administered A(1–7) subcutaneously for 4 weeks.

Figure 2

Time versus A(1–7) concentration curve in rats, where the closed circles represent day 0, whereas the open squares represents day 27.

Figure 3

Concentration versus time for each individual canine. Plasma A(1–7) concentration on day 0 is represented by the closed circles and A(1–7) concentration on day 27 is represented by the open squares.