Substituted imidazole compounds include agents which have therapeutically useful, H2 antagonist, anticonvulsant, antiinflammatory and sedative-hypnotic properties. N-substituted imidazoles are best known for their antimycotic activity. N- substituted imidazoles, although mostly investigated for drug interactions resulting from their inhibitory properties have recently become known as powerful inducers of hepatic oxidative drug metabolism. An investigation of the conditions and characteristics necessary for induction and their relationship to inhibitory properties, and the relevance of both processes to drug interactions and drug toxicity is the major thrust of this proposal. The dose, route and duration of N-substituted imidazole administration necessary for the induction, especially the """"""""dose dependent isozyme induction"""""""" and """"""""high magnitude"""""""" induction characteristics of Phase I cytochrome P-450 oxidations as well as changes in Phase II glutathione, sulfate and glucuronic acid conjugations in male rats will be determined. Hepatic concentrations of the N-substituted imidazoles will be monitored. New N-substituted imidazoles will be synthesized to augment those commercially available in attempts to delineate the characteristics of the molecule necessary for the various induction characteristics. The cytochrome P-450 isozymes and classes of UDP-glucuronosyl-transferases induced will be compared with those present after administration of classical inducing agents. New isozymes or novel induction profiles of known isozymes of cytochrome P-450 will be sought using characteristic monooxygenase activities and SDS polyacrylamide gel electrophoresis of microsomal fractions anion exchange HPLC fractionation, (also coupled with SDS-polyacrylamide gel electrophoresis) and reconstitution of enzymatic activity. The relationship between the cytochrome P-450 isozyme(s) which are inhibited and isozymes which are induced by N-substituted imidazoles will be investigated. The effect of inhibition and induction of Phase I oxidation and any changes in Phase II conjugations on the pharmacological effect and hepatotoxicity of model compounds will be investigated. The overall findings will provide greater accuracy to the prediction of drug-drug interactions likely to arise from the therapeutic use of N- substituted imidazoles.
