NOVEL CHARACTERISTICS OF 1-IMIDAZOLE ENZYME INDUCTION

取代的咪唑化合物包括具有以下性质的试剂： 治疗上有用的，H2拮抗剂，抗惊厥剂， 镇静和催眠的特性。 n取代 咪唑类化合物因其抗霉菌活性而广为人知。 不，不 取代的咪唑类，虽然大多数研究用于药物 由其抑制特性产生的相互作用 最近被认为是肝脏氧化的强诱导剂， 药物代谢 调查的条件和 归纳所需的特征及其与 抑制特性，以及这两个过程与药物的相关性 相互作用和药物毒性是该提案的主要目的。 N-取代咪唑的剂量、途径和持续时间 诱导所必需的给药，特别是“剂量”， 依赖性同工酶诱导”和“高强度”诱导 I相细胞色素P-450氧化的特征以及 II相谷胱甘肽、硫酸盐和葡萄糖醛酸的变化 将测定雄性大鼠中的接合。 肝 将监测N-取代的咪唑的浓度。 将合成新的N-取代的咪唑以增加 那些商业上可获得的，试图描绘 分子的各种特性所必需的 感应特性 细胞色素P-450同工酶和 诱导的UDP-葡萄糖醛酸基转移酶的种类将是 与给予经典的 诱导剂 新的同工酶或新的诱导谱 细胞色素P-450的已知同工酶将使用 特征单加氧酶活性和SDS聚丙烯酰胺 微粒体组分凝胶电泳阴离子交换HPLC 分级分离，（也与SDS-聚丙烯酰胺凝胶结合 电泳）和酶活性的重建。 的 细胞色素P-450同工酶之间的关系， 抑制和同工酶，诱导的N-取代 将研究咪唑。 抑制作用和 I相氧化的诱导和II相的任何变化 偶联物的药理作用和肝毒性 将研究模型化合物。 总体调查结果将 为药物-药物预测提供更高的准确性， 相互作用可能产生的治疗使用N- 取代的咪唑。

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.