Bioavailability of Orally Administered Des-Aspartate-Angiotensin I in Human Subjects
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ORIGINAL RESEARCH ARTICLE
Bioavailability of Orally Administered Des-Aspartate-Angiotensin I in Human Subjects Kok-Onn Lee1 • Edmund Feng Tian2 • Martin Hui Cai2 • Hong Wang3,5 Yiong-Huak Chan4 • Meng-Kwoon Sim5,6
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Ó The Author(s) 2017. This article is an open access publication
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 & Meng-Kwoon Sim [email protected] 1
Department of Medicine, National University of Singapore, 1E Kent Ridge Road, NUHS Tower Block Level 10, Singapore 119228, Singapore
2
School of Applied Science, Temasek Polytechnic, 21 Tampines Avenue 1, Singapore 529757, Singapore
3
Singapore Nuclear Research and Safety Initiative, National University of Singapore, 1 CREATE Way, #04-01 CREATE Tower, Singapore 138602, Singapore
4
Biostatistics Unit, Yong Loo Lin School of Medicine, National University Health System, 1E Kent Ridge Road, NUHS Tower Block Level 11, Singapore 119228, Singapore
5
Department of Pharmacology, Yong Loo Lin School of Medicine, Block MD 3 Level 4 #04-01, 16 Medical Drive, Singapore 117600, Singapore
6
SimPharma, 60 Paya Lebar Road #12-55, Paya Lebar Square, Singapore 409051, Singapore
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. Key Points The bioavailability of orally administered desaspartate-angiotensin I (DAA-I) was investigated in human subjects. Prostaglandin E2 metabolite (PGEM), a stable metabolite derivative of PGE2 was measured as a biomarker of DAA-I in plasma samples obtained from 15 subjects in a single-dose phase I trial on DAA-I. Plasma of two of the three subjects who were ad
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