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


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Bae
Soo H
SH
College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, South Korea.
Bae
Soo K
SK
Lee
Myung G
MG
D000818:Animals; D019540:Area Under Curve; D002927:Cimetidine / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D008658:Inactivation, Metabolic; D008099:Liver / Q000378:metabolism*; D008297:Male; D008861:Microsomes; D010726:Phosphodiesterase Inhibitors / Q000378:metabolism / Q000493:pharmacokinetics*; D010879:Piperazines / Q000378:metabolism / Q000493:pharmacokinetics*; D011687:Purines / Q000378:metabolism / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D000068677:Sildenafil Citrate; D013450:Sulfones / Q000378:metabolism / Q000493:pharmacokinetics*; D014217:Troleandomycin / Q000494:pharmacology*
D004791:Enzyme Inhibitors; D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D002927:Cimetidine; D003577:Cytochrome P-450 Enzyme System; D000068677:Sildenafil Citrate; D014217:Troleandomycin