INDUCTION AND INHIBITION OF RAT HEPATIC DRUG-METABOLISM BY N-SUBSTITUTED IMIDAZOLE DRUGS

  • 1 May 1987
    • journal article
    • research article
    • Vol. 15  (3) , 335-343
Abstract
Three daily administrations of N-substituted imidazole antimycotics, clotrimazole (CloTZ, 75 mg/kg/day), micronazole (MCZ, 150 mg/kg/day), or tioconazole (TCZ, 150 mg/kg/day), but not the 4,5-disubstituted imidazole cimetidine (350 mg/kg/day) or imidazole (200 mg/kg/day for 4 days), induced rat hepatic cytochrome P-450 and other drug-metabolizing enzymes. These findings paralleled in vitro observations where CloTZ, MCZ, and TCZ were several orders of magnitude more potent as inhibitors of p-nitroanisole O-demethylase activity in control male rat liver microsomes than cimetidine or imidazole. Although no marked difference in inhibitory potency was evident among the N-substituted imidazoles, there were qualitative and quantitative differences in the profiles and extents of induction of various cytochrome P-450-dependent monooxygenases and Phase II conjugation enzymes. Cytochrome P-450 was elevated dramatically by CloTZ (3-4 times the control) and to a lesser extent by MCZ and TCZ (= 1.5 times the control). For all agents, there was an increase in metyrapone binding approximately equivalent to the additional (i.e. above control) cytochrome P-450. Despite the large difference in cytochrome P-450 induction by CloTZ, MCZ, and TCZ, these agents elevated p-nitroanisole demethylase and aniline hydroxylase to similar extents (3-5 .times. 1-2 .times. control, respectively). All agents induced erythromycin and ethylmorphine demethylation in proportion to cytochrome P-450. Ethoxyresorufin O-de-ethylation was not substantially affected by any agent. Large differences in the extent and specificity of induction of microsomal glucuronide conjugations were also evident. TCZ, only a mild monooxygenase inducer, was the most effective inducer of UDP-glucuronosyltransferase, dramatically elevating activity toward p-nitrophenol (3.5 .times. control), morphine (4 .times. control), and 1-naphthol (2.5 .times. control). The most effective cytochrome P-450 inducer, CloTZ, increased UDP-glucuronosyltransferase toward these three substrates to an extent much less than TCZ. MCZ induced p-nitrophenol and naphthol (1.4 .times. and 1.8 .times. control, respectively), but not morphine glucuronidation. All four N-substituted imidazoles increased cytosolic glutathione S-transferase and decreased sulfotransferase activities. The data indicate that, as inducing agents, closely related imidazoles cannot be considered as a single group and that induction of Phase I and Phase II enzymes may be independent of one another.