Induction potential of fluconazole toward drug-metabolizing enzymes in rats.
The induction of drug-metabolizing enzymes in rat liver was studied after subchronic administration of the new triazole antifungal agent fluconazole. The administered doses were 10, 40, and 160 mg/kg per day for 7 days. Fluconazole behaved as a high-magnitude inducer and significantly increased cytochrome P-450 concentrations already at 10 mg/kg (+42%). Cytochrome P-450 induction by fluconazole was dose dependent and reached a value of 302% of the control value at the dose of 160 mg/kg. The induction effects on cytochrome P-450 were also reflected in the drug-metabolizing enzyme activities in hepatic microsomes of pretreated rats. Fluconazole (160 mg/kg per day) preferentially induced the demethylase activities of N,N-dimethylaniline and p-nitroanisole to 258 and 281% of the control values, respectively. The detoxification enzyme UDP-glucuronosyltransferase was significantly lowered by fluconazole at the highest dose. A possible link between the induction potential and the pharmacokinetic properties of triazole antifungal agents is discussed.
Lavrijsen
K L
KL
Department of Drug Metabolism and Pharmacokinetics, Janssen Research Foundation, Beerse, Belgium.
Van Houdt
J M
JM
Van Dyck
D M
DM
Meuldermans
W E
WE
Heykants
J J
JJ
D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004790:Enzyme Induction; D015725:Fluconazole / Q000378:metabolism*; D007527:Isoenzymes / Q000378:metabolism; D008099:Liver / Q000201:enzymology; D008297:Male; D009929:Organ Size; D051381:Rats; D011919:Rats, Inbred Strains
D007527:Isoenzymes; D015725:Fluconazole; D003577:Cytochrome P-450 Enzyme System