期刊
EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES
卷 56, 期 -, 页码 113-119出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.ejps.2014.01.012
关键词
Hypertension; Lisinopril-tryptophan; Pharmacokinetic analysis; LC-MS/MS method
资金
- Wellcome Trust
- University of Cape Town (EDS, ND)
- South African Medical Research Council
- South African Research Chairs Initiative of the Department of Science and Technology
- University of Cape Town (KC)
Angiotensin-converting enzyme (ACE, EC 3.4.15.1) is a metallopeptidase comprised of two homologous catalytic domains (N- and C-domains). The C-domain cleaves the vasoactive angiotensin II precursor, angiotensin I, more efficiently than the N-domain. Thus, C-domain-selective ACE inhibitors have been designed to investigate the pharmacological effects of blocking the C-terminal catalytic site of the enzyme and improve the side effect profile of current ACE inhibitors. Lisinopril-tryptophan (LisW-S), an analogue of the ACE inhibitor lisinopril, is highly selective for the C-domain. In this study, we have analysed the ex vivo domain selectivity and pharmacokinetic profile of LisW-S. The IC50 value of LisW-S was 38.5 nM in rat plasma using the fluorogenic substrate Abz-FRKP(Dnp)P-OH. For the pharmacokinetics analysis of LisW-S, a sensitive and selective LC-MS/MS method was developed and validated to determine the concentration of LisW-S in rat plasma. LisW-S was administered to Wistar rats at a dose of 1 mg/kg bodyweight intravenously, 5 mg/kg bodyweight orally. The C-max obtained following oral administration of the drug was 0.082 mu M and LisW-S had an apparent terminal elimination half-life of around 3.1 h. The pharmacokinetic data indicate that the oral bioavailability of LisW-S was approximately 5.4%. These data provide a basis for better understanding the absorption mechanism of LisW-S and evaluating its clinical application. (C) 2014 Elsevier B.V. All rights reserved.
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