Effect of hepatic CYP inhibitors on the metabolism of sildenafil and formation of its metabolite, N-desmethylsildenafil, in rats in vitro and in vivo

College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, South Korea.
The Journal of pharmacy and pharmacology 12/2009; 61(12):1637-42. DOI: 10.1211/jpp/61.12.0008
Source: PubMed


It has been reported that hepatic cytochrome P450 (CYP)2C9 and CYP3A4 are responsible for the metabolism of sildenafil and formation of its metabolite, N-desmethylsildenafil, in humans. However, in-vivo studies in rats have not been reported.
Sildenafil (20 mg/kg) was administered intravenously to rats pretreated with sulfaphenazole, cimetidine, quinine hydrochloride or troleandomycin, inhibitors of CYP2C6, CYP2C11, CYP2D subfamily and CYP3A1/2, respectively. In-vitro studies using rat liver microsomes were also performed.
The area under the plasma-concentration time curve (AUC) was increased and clearance of sildenafil decreased in rats pretreated with cimetidine or troleandomycin. The AUC ratio for N-desmethylsildenafil (0-4 h) : sildenafil (0-infinity) was significantly decreased only in rats pretreated with cimetidine. Similar results were obtained in the in-vitro study using rat liver microsomes.
Sildenafil is metabolised via hepatic CYP2C11 and 3A1/2, and N-desmethylsildenafil is mainly formed via hepatic CYP2C11 in rats. Thus, rats could be a good model for pharmacokinetic studies of sildenafil and N-desmethylsildenafil in humans.

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    • "Results that are supported by previous pharmacokinetic studies, in which SDF administered orally to rats showed that the principal route of metabolism of SDF is the N-demethylation mediated by cytochrome P450 3A1/2 and 2C11, with desmethylSDF as the major circulating metabolite [9] [10]. However, our data also demonstrated the presence of O-desethylSDF, a metabolite of SDF that did not correspond with the rat plasma metabolites previously described. "
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