title: Comparison of two azole antifungal drugs, ketoconazole, and fluconazole, as modifiers of rat hepatic monooxygenase activity.
abstract: The mechanism of action of azole antifungal agents is believed to involve inhibition of fungal cytochrome P-450, and, therefore, an investigation of the interaction of these drugs with mammalian cytochrome P-450 systems should provide some indication of their selectivity as antifungal agents. The ability of ketoconazole and fluconazole, the latter representing a new generation of triazole antifungal agents, to modify rat mixed function oxidase activity has been investigated in vitro with hepatic microsomes and in vivo using a N-methyl-[14C] antipyrine breath test. As a measure of selectivity the results have been compared with antifungal potency. Ketoconazole is more potent than fluconazole by an order of magnitude in inhibiting metabolism by O-dealkylation of ethoxycoumarin, methoxycoumarin and ethoxyresorufin (IC50 values of 6, 5 and 130 microM for ketoconazole respectively). The effects on the regio- and stereospecific hydroxylation of [14C] testosterone were also measured; the IC50 values for inhibition of total testosterone metabolism were 0.1 mM and greater than 3 mM for ketoconazole and fluconazole respectively. Marked selectivity differences were observed for the two drugs as indicated by ketoconazole being a potent inhibitor of 7 alpha-hydroxylation of testosterone (IC50 20 microM) while fluconazole did not inhibit this activity at 3 mM. In vivo investigations using a range of doses confirmed their ranking for inhibitory potency; the ED50 values for maximum demethylation rate were 17 mumol/kg and greater than 60 mumol/kg for ketoconazole and fluconazole respectively. Thus fluconazole has a lower propensity to interact with rat hepatic cytochrome P-450 and can be considered a more selective antifungal agent as its in vivo antifungal potency is an order of magnitude greater than ketoconazole.
authors.affiliation: Department of Pharmacy, University of Manchester, U.K.
authors.forename: J B
authors.initials: JB
authors.lastname: Houston
authors.forename: M J
authors.initials: MJ
authors.lastname: Humphrey
authors.forename: D E
authors.initials: DE
authors.lastname: Matthew
authors.forename: M H
authors.initials: MH
authors.lastname: Tarbit
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology*; D015725:Fluconazole; D007654:Ketoconazole / Q000494:pharmacology*; D007700:Kinetics; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology*; D006899:Mixed Function Oxygenases / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D013379:Substrate Specificity; D013739:Testosterone / Q000378:metabolism; D014230:Triazoles / Q000494:pharmacology*
chemical_list: D000935:Antifungal Agents; D014230:Triazoles; D013739:Testosterone; D015725:Fluconazole; D006899:Mixed Function Oxygenases; D007654:Ketoconazole