Effects of enzyme inducers and inhibitors on the pharmacokinetics of intravenous torasemide in rats.
In order to find whether torasemide is metabolized via CYP isozymes in rats, torasemide at a dose of 2mg/kg was infused in rats pretreated with SKF 525-A, a non-specific CYP isozyme inhibitor in male Sprague-Dawley rats. The total area under the plasma concentration-time curve from time zero to time infinity (AUC) of torasemide was significantly greater in rats pretreated with SKF 525-A (a non-specific CYP isozyme inhibitor in rats) than that in control rats (3570 versus 1350 microg min/ml). This indicated that torasemide is metabolized via CYP isozymes in rats. Hence, torasemide was infused in rats pretreated with various enzyme inducers and inhibitors to find what types of CYP isozymes are involved in the metabolism of torasemide in rats. The AUC values were not significantly different in rats pretreated with 3-methylcholanthrene, phenobarbital, isoniazid, quinine and troleandomycin (main inducers of CYP1A1/2, CYP2B1/2, and CYP2E1, and main inhibitors of CYP2D1 and CYP3A1/2 in rats, respectively) compared with those in respective control rats. However, in rats pretreated with dexamethasone (a main inducer of CYP3A1/2 in rats), the AUC was significantly smaller than that in control rats (1290 versus 1590 microg min/ml). Dexamethasone probably also induces rat CYP2C11; this could be due to an increase in CYP2C11 in rats pretreated with dexamethasone. It has been reported from our laboratories that in rats pretreated with sulfaphenazole (a main inhibitor of CYP2C11 in rats) the AUC was significantly greater than that in control rats (2970 versus 1610 microg min/ml). The above data suggested that torasemide could be metabolized in male rats mainly via CYP2C11.
Lee
Dae Y
DY
College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, San 56-1, Shinlim-Dong, Kwanak-Gu, Seoul 151-742, South Korea.
Lee
Shin J
SJ
Lee
Myung G
MG
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000502:physiology; D051544:Cytochrome P-450 CYP3A; D000072467:Cytochrome P450 Family 2; D003907:Dexamethasone / Q000494:pharmacology; D004790:Enzyme Induction; D008297:Male; D008565:Membrane Proteins / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D039181:Steroid 16-alpha-Hydroxylase / Q000502:physiology; D013449:Sulfonamides / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000077786:Torsemide
D008565:Membrane Proteins; D013449:Sulfonamides; D003907:Dexamethasone; D001189:Aryl Hydrocarbon Hydroxylases; C450279:CYP2C11 protein, rat; C465260:Cyp3a2 protein, rat; C465138:Cyp3a23-3a1 protein, rat; D051544:Cytochrome P-450 CYP3A; D000072467:Cytochrome P450 Family 2; D039181:Steroid 16-alpha-Hydroxylase; D000077786:Torsemide