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.

Vasoconstrictor and Pressor Effects of Des-Aspartate-Angiotensin I in Rat

“…Similar effects were observed in rats, in which pressor and steroidogenic actions of DAA-I were dependent on the hydrolysis of (DAA-1) to angiotensin III [ 42 ]. Uninephrectomized fawn-hooded hypertensive rats treated with low and high doses of DAA-I also showed a rise in BP [ 43 ], whereas Lee et al [ 14 , 15 ] observed no BP changes in healthy subjects given a single oral dose of DAA-I at different concentrations. Therefore, besides the direct effects of DAA-I reported in the present study, it can also be considered a precursor for the biological effects of angiotensin III.…”

“…In a later investigation, Sim and Qui [ 11 ] found similar plasma concentrations of DAA-I, Ang I, Ang II, and Ang III in both Sprague–Dawley and Wistar-Kyoto (WKY) rats. DAA-I has been demonstrated to be active when administered orally [ 12 , 13 , 14 , 15 ], showing a rapid systemic metabolism when infused into the circulation or orally administered in humans [ 14 , 16 ].…”