EFFECT OF MULTIPLE DOSES OF KETOCONAZOLE ON CYTOCHROME P450 3A ACTIVITY

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。细胞色素P450(CYP)3A酶是成人肝脏和小肠中含量最丰富的CYP酶。细胞色素P3A酶参与了超过50%的代谢药物的生物转化。临床上观察到的许多药物-药物相互作用(DDI)都是由于改变这些酶的活性而产生的。酮康唑在体内是一种很强的细胞色素P3A活性抑制剂，可导致许多DDI，但目前尚不清楚这种作用是否在治疗常用剂量范围内呈剂量依赖关系。临床试验的模拟表明，与持续一周的每天400毫克相比，每天两次服用200毫克的患者可能会获得与酮康唑相同的治疗益处，并且药物相互作用更少。然而，这些酮康唑给药策略的DDI潜力还没有在人体中进行直接比较。我们计划以咪达唑仑为典型的细胞色素P3A底物，研究酮康唑400 mg qd和200 mg bid对肝脏和肠道细胞色素P3A活性的影响。酮康唑是一种比CYP3A5更有效的抑制剂，并且后者是多态表达的(33%的高加索人和70%的非裔美国人)。因此，我们计划检查酮唑唑的抑制效力是否依赖于允许CYP3A5表达的基因类型的存在。这将是一项针对24名健康志愿者的交叉研究。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The cytochrome P450 (CYP) 3A enzymes are the most abundant CYP enzymes in adult human liver and small intestine. The CYP3A enzymes are involved in the biotransformation of more than 50% of all metabolized drugs. Many drug-drug interactions (DDI) observed clinically result from altering the activities of these enzymes. Ketoconazole is a strong inhibitor of CYP3A activity in vivo and results in many DDIs but it is unclear whether this effect is dose dependent within the range of doses commonly employed therapeutically. Simulations of clinical trials have suggested that patients may receive the same therapeutic benefit from ketoconazole and less drug interactions at 200 mg twice a day compared to 400 mg once a day for one week. However, the DDI potential of these dosing strategies for ketoconazole have not been directly compared in humans. We plan to determine the effect of ketoconazole 400 mg QD and 200 mg BID on hepatic and intestinal CYP3A activity using midazolam as a prototypical CYP3A substrate. Ketoconazole is a more potent inhibitor of CYP3A4 than CYP3A5 and the latter enzyme is polymorphically expressed (33% of Caucasians and 70% of African Americans). We therefore plan to examine whether the inhibitory potency of ketozonazole is dependent on the presence of genotypes that allow CYP3A5 expression. This will be a cross-over study in 24 healthy volunteers.