title: Pharmacokinetic evaluation of lisinopril-tryptophan, a novel C-domain ACE inhibitor.
abstract: 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 Cmax obtained following oral administration of the drug was 0.082 μM 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.
authors.affiliation: Division of Clinical Pharmacology, University of Cape Town, Observatory, Cape Town 7925, South Africa.
authors.forename: Paolo
authors.initials: P
authors.lastname: Denti
authors.affiliation: Cardiovascular Research Unit, Chris Barnard Division of Cardiothoracic Surgery, University of Cape Town, Department of Health Sciences, Cape Town, South Africa.
authors.forename: Sarah-Kate
authors.initials: SK
authors.lastname: Sharp
authors.affiliation: Institute of Infectious Disease and Molecular Medicine, Division of Medical Biochemistry, University of Cape Town, Observatory, Cape Town 7925, South Africa.
authors.forename: Wendy L
authors.initials: WL
authors.lastname: Kröger
authors.affiliation: Institute of Infectious Disease and Molecular Medicine, Division of Medical Biochemistry, University of Cape Town, Observatory, Cape Town 7925, South Africa.
authors.forename: Sylva L
authors.initials: SL
authors.lastname: Schwager
authors.affiliation: Department of Chemistry, Institute of Infectious Disease and Molecular Medicine (IDM) and South African Medical Research Council Drug Discovery and Development Research Unit, University of Cape Town, Rondebosch 7701, South Africa.
authors.forename: Aman
authors.initials: A
authors.lastname: Mahajan
authors.affiliation: Department of Chemistry, Institute of Infectious Disease and Molecular Medicine (IDM) and South African Medical Research Council Drug Discovery and Development Research Unit, University of Cape Town, Rondebosch 7701, South Africa.
authors.forename: Mathew
authors.initials: M
authors.lastname: Njoroge
authors.affiliation: Division of Clinical Pharmacology, University of Cape Town, Observatory, Cape Town 7925, South Africa.
authors.forename: Liezl
authors.initials: L
authors.lastname: Gibhard
authors.affiliation: Division of Clinical Pharmacology, University of Cape Town, Observatory, Cape Town 7925, South Africa.
authors.forename: Ian
authors.initials: I
authors.lastname: Smit
authors.affiliation: Department of Chemistry, Institute of Infectious Disease and Molecular Medicine (IDM) and South African Medical Research Council Drug Discovery and Development Research Unit, University of Cape Town, Rondebosch 7701, South Africa.
authors.forename: Kelly
authors.initials: K
authors.lastname: Chibale
authors.affiliation: Division of Clinical Pharmacology, University of Cape Town, Observatory, Cape Town 7925, South Africa.
authors.forename: Lubbe
authors.initials: L
authors.lastname: Wiesner
authors.affiliation: Institute of Infectious Disease and Molecular Medicine, Division of Medical Biochemistry, University of Cape Town, Observatory, Cape Town 7925, South Africa. Electronic address: edward.sturrock@uct.ac.za.
authors.forename: Edward D
authors.initials: ED
authors.lastname: Sturrock
authors.affiliation: Cardiovascular Research Unit, Chris Barnard Division of Cardiothoracic Surgery, University of Cape Town, Department of Health Sciences, Cape Town, South Africa. Electronic address: neil.davies@uct.ac.za.
authors.forename: Neil H
authors.initials: NH
authors.lastname: Davies
mesh_terms: D000806:Angiotensin-Converting Enzyme Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology; D000818:Animals; D018938:Caco-2 Cells; D020134:Catalytic Domain; D006801:Humans; D017706:Lisinopril / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology; D008297:Male; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism; D017208:Rats, Wistar; D014364:Tryptophan / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D014364:Tryptophan; D017706:Lisinopril; D007703:Peptidyl-Dipeptidase A
keywords: Hypertension; LC–MS/MS method; Lisinopril-tryptophan; Pharmacokinetic analysis