title: Biotransformation of sildenafil in the male rat: evaluation of drug interactions with testosterone and carbamazepine.
abstract: The biotransformation of sildenafil to its major circulating metabolite, UK-103,320, was studied in male rat liver microsomes. The conversion of sildenafil to UK-103,320 by rat microsomes followed Michaelis-Menten kinetics, for which the parameters were V(max) = 1.96 microM/minand K(m) = 27.31 microM. Using substrates of CYP3A4 of testosterone and carbamazepine, the active sites on CYP3A4 responsible for metabolizing sildenafil were also evaluated. Sildenafil biotransformation was inhibited in the individual presence of testosterone and carbamazepine. The results showed drug interaction was observed in the sildenafil-testosterone and sildenafil-carbamazepine. Although testosterone and carbamazepine can inhibit sildenafil demethylation in concentration- and incubation time-dependent manners, sildenafil did not inhibit testosterone hydroxylation or carbamazepine epoxidation. These results may be explained by a model in which multiple substrates or ligands can concurrently bind to the active site of a single CYP3A4 molecule. However, the contribution of separate allosteric sites and conformational heterogeneity to the atypical kinetics of CYP3A4 cannot be ruled out in this study.
authors.affiliation: College of Pharmacy, Taipei Medical University, Taipei, Taiwan, ROC.
authors.forename: Ying-Ku
authors.initials: YK
authors.lastname: Lin
authors.forename: Ming-Thau
authors.initials: MT
authors.lastname: Sheu
authors.forename: Thau-Zong
authors.initials: TZ
authors.lastname: Tzen
authors.forename: Hsiu-O
authors.initials: HO
authors.lastname: Ho
mesh_terms: D000818:Animals; D001711:Biotransformation / Q000187:drug effects / Q000502:physiology; D002220:Carbamazepine / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004347:Drug Interactions / Q000502:physiology; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D010879:Piperazines / Q000493:pharmacokinetics*; D011687:Purines / Q000493:pharmacokinetics; D051381:Rats; D017208:Rats, Wistar; D000068677:Sildenafil Citrate; D013450:Sulfones / Q000493:pharmacokinetics*; D013739:Testosterone / Q000493:pharmacokinetics*
chemical_list: D010879:Piperazines; D011687:Purines; D013450:Sulfones; D002220:Carbamazepine; D013739:Testosterone; D000068677:Sildenafil Citrate