NOVEL CHARACTERISTICS OF 1-IMIDAZOLE ENZYME INDUCTION

取代咪唑化合物包括具有 治疗上有用，H2受体拮抗剂，抗惊厥药， 具有抗炎和镇静催眠作用。N-取代 咪唑类化合物最为人所知的是其抗真菌活性。vt.N- 取代的咪唑类化合物，尽管主要用于药物研究 由于它们的抑制特性而产生的相互作用 最近被认为是肝脏氧化的强大诱导剂 药物新陈代谢。对条件和条件的调查 归纳法的必要特征及其与 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这项提议的主要主旨。 N-取代咪唑的剂量、途径和持续时间 诱导所需的用药，尤其是“剂量” “依赖同工酶诱导”和“高幅度”诱导 I相细胞色素P-450的氧化特性以及 谷胱甘肽、硫酸盐和葡萄糖醛酸的变化 雄性大鼠的结合将被确定。肝脏 将监测N-取代咪唑的浓度。 将合成新的N-取代咪唑以增强 这些商业上可用的东西试图描绘出 各种疾病所需的分子的特征 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类别将是 与服用经典型药物后的患者相比 诱导剂。新的同工酶或新的诱导谱 已知的细胞色素P-450同工酶将使用 特征单加氧酶活性与十二烷基硫酸钠-聚丙烯酰胺 微粒体组分阴离子交换高效液相色谱凝胶电泳法 分级，(也与十二烷基硫酸钠-聚丙烯酰胺凝胶相结合 电泳法)和酶活性的重建。这个 细胞色素P-450同工酶(S)与 N-取代诱导的抑制酶和同工酶 将对咪唑类药物进行调查。抑制和抑制的效果 第一阶段氧化的诱导和第二阶段的任何变化 结合物的药理作用和肝毒性研究 将对模型化合物进行研究。总体调查结果将 为药物预测提供更高的准确性 N-的治疗性使用可能产生的相互作用 取代咪唑类化合物。

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.