Bioavailability of Orally Administered Des-Aspartate-Angiotensin I in Human Subjects

Abstract

In an earlier single-dose escalation study to evaluate the safety and pharmacokinetics of orally administered des-aspartate-angiotensin I (DAA-I) in healthy subjects, the plasma level of DAA-I could not be determined because DAA-I is rapidly degraded in the circulation. The present study investigated the oral bioavailability of DAA-I by measuring the prostaglandin E₂ metabolite (PGEM) in the plasma samples of the same trial. PGEM is a stable derivative of PGE₂, which has been shown to be a biomarker of DAA-I. The data show that plasma from two of the three subjects who were orally administered the efficacious preclinical dose of 0.70 mg/kg DAA-I exhibited a significant PGEM peak at 5-6 h postdose. Plasma of subjects who were administered 0.08 and 1.5 mg/kg DAA-I, the subefficacious and two-times efficacious dose, respectively, did not exhibit a similar PGEM peak. This observation is concordant with the known in vivo actions of DAA-I, especially its hypoglycemic action where maximum efficacy occurred at a dose of 0.7 mg/kg, and decreased to nil at the two-times efficacious dose. The onset of the PGEM peak at 5-6 h postdose was closed to the 4-h onset of absorption of [C¹⁴]DAA-I seen in preclinical rat studies, albeit the absorption kinetics between rodents and humans are not identical. The occurrence of polymorphism of enzymes involved in the formation and degradation of PGE₂ is common, and this has been attributed to contributing to the variation in response, onset and peak PGEM observed among the three subjects who were administered the efficacious dose.

Fig. 1

Plasma PGEM concentrations. A5, B2, B6, C2 and C5 were placebo samples, and samples in the upper, middle and lower plots were from subjects who were administered 0.08, 0.70, and 1.5 mg/kg DAA-I, respectively. * Indicates significantly greater than the corresponding values of B1, B2, B4 and B6 (p < 0.01), ^# indicates significantly greater than the corresponding values of B2 and B6 (p < 0.01)