title: Lack of male-female differences in disposition and esterase hydrolysis of ramipril to ramiprilat in healthy volunteers after a single oral dose.
abstract: The objective of this study was to identify differences in disposition and esterase hydrolysis of ramipril between male and female volunteers. Plasma concentration and area under the concentration-time curve until the last measured concentration (AUCt) data of ramipril and its active metabolite ramiprilat (-diacid) were obtained from a randomised, cross-over bioequivalence study in 36 subjects (18 females and 18 males). Participants received a single 5-mg oral dose of two different formulations of ramipril (Formulation I and II). Plasma ramipril and ramiprilat concentrations were determined according to validated methods involving liquid chromatography-mass spectrometry. A total number of 2 x 34 available plasma concentration-time curves of both the parent drug and the metabolite could be analysed, and variations (50-100% coefficient of variation [CV]) in plasma concentrations of both parent drug and metabolite were found. With both the formulations, the mean plasma concentrations-time curves of males and females were identical. The groups of female and male volunteers showed similar yields (AUCt = microg x h/L) of the metabolite ramiprilat (p = 0.37); however, females showed a higher AUCt/kg than males (p = 0.046). This difference was solely attributed to the difference in body weight between males and females (p = 0.00049). In both male and female groups, a subject-dependent yield of active metabolite ramiprilat was demonstrated, which was independent of the formulation. There is a large variation in the ramiprilat t1/2beta (50-60% CV). There is a group of subjects who showed a t1/2beta of approximately 80 h (15% CV), and two apparent groups with a longer t1/2beta for each formulation (124 h, 22.5% CV; 166 h, 21.6% CV, respectively, p = 0.0013). This variation in the terminal half-life of ramiprilat is not sex related. In all three groups of half-lives, the corresponding Cmax values (mean +/- SD) of ramiprilat in males and females were identical. Thus, with identical Cmax and half-lives, the difference found in the AUCt/kg of ramiprilat must be due to the difference in dose, as the consequence of the difference in body weight, following a standard dose of 5 mg in both males and females. This study showed clearly that despite subject-dependent hydrolysis of ramipril to the active metabolite ramiprilat, the variability in the rate of hydrolysis between males and females is similar. With a fixed dose (5 mg), females received a higher dose/kg than males and consequently showed a higher AUCt/kg of the active metabolite ramiprilat.
authors.affiliation: Institute for Anaesthesiology, University Medical Centre Nijmegen Sint Radboud, Nijmegen,The Netherlands. T.Vree@anes.umcn.nl
authors.forename: Tom B
authors.initials: TB
authors.lastname: Vree
authors.forename: Erik
authors.initials: E
authors.lastname: Dammers
authors.forename: Ivan
authors.initials: I
authors.lastname: Ulc
authors.forename: Stefan
authors.initials: S
authors.lastname: Horkovics-Kovats
authors.forename: Miroslav
authors.initials: M
authors.lastname: Ryska
authors.lastname: Merkx
authors.lastname: Ijsbrand
mesh_terms: D000328:Adult; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000493:pharmacokinetics*; D018592:Cross-Over Studies; D004064:Digestive System / Q000201:enzymology; D004950:Esterases / Q000097:blood / Q000378:metabolism*; D005260:Female; D006801:Humans; D006868:Hydrolysis; D008099:Liver / Q000201:enzymology; D008297:Male; D008875:Middle Aged; D017257:Ramipril / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*; D012727:Sex Characteristics
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; C052549:ramiprilat; D004950:Esterases; D017257:Ramipril