Lack of Male-Female Differences in Disposition and Esterase Hydrolysis of Ramipril to Ramiprilat in Healthy Volunteers after a Single Oral Dose. (2003)

• Record Type: Journal Article
• Authors: Vree, Tom B.; Dammers, Erik; Ulc, Ivan; Horkovics-Kovats, Stefan; Ryska, Miroslav; Merkx, IJsbrand
• Is Part Of: TheScientificWorldjournal. Volume 3(2003)
• Page Start: 1344
• Page End: 1358
• Publication Date: 2003
• Subjects: ramipril -- ramiprilat -- pharmacokinetics -- liver -- gut -- hydrolysis -- plasma concentration -- male-female -- elimination half-life; Science -- Periodicals; Technology -- Periodicals; Medicine -- Periodicals; 505
• DOI: 10.1100/tsw.2003.122
• Languages: English
• ISSNs: 2356-6140

Abstract

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 � 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 = mg.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 t1/2β (50�60% CV). There is a group of subjects who showed a t1/2β of approximately 80 h (15% CV), and two apparent groups with a longer t1/2β 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.