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

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.