THE EFFECT OF CONCOMITANT ADMINISTRATION OF ERYTHROMYCIN AND DILTIAZEM ON CYP

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 细胞色素P450 3A(CYP3A)亚家族是药物代谢中最重要的亚家族之一，负责多种内源性和外源性化合物的代谢。细胞色素P3A亚家族成员(细胞色素P3A4和细胞色素P3A5)在肝脏和小肠壁中大量表达，是药物相互作用的重要部位。红霉素在体外通过在人肝微粒体中形成代谢中间复合体(MIC)来抑制CYP3A4。药代动力学表明，红霉素轻微但显著地改变了静脉和口服咪达唑仑的药代动力学，使咪达唑仑的全身清除量减少54%，口服生物利用度增加两倍。同样，体外实验表明，地尔硫卓通过形成MIC抑制细胞色素P3A4。体内研究报告了咪达唑仑和地尔硫卓之间温和的药物相互作用，当两者都作为单剂量口服时，地尔硫卓显著增加了曲线下的面积，延长了咪达唑仑的消除半衰期。然而，长期服用地尔硫卓对咪达唑仑药代动力学的影响尚不清楚。此外，尽管在当代药物治疗中，联合使用两种适度的抑制剂对CYP3A底物的药代动力学的影响是常见的，但其影响尚不清楚。重要的是，抑制剂组合的影响可能是复杂的，并且不容易从二元药物-药物相互作用研究中预测出来。为此，我们想要研究红霉素和地尔硫卓单独和联合使用对咪达唑仑药物动力学的影响。

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 3A (CYP3A) subfamily of enzymes is one of the most important in drug metabolism and is responsible for the metabolism of a wide variety of endogenous and exogenous compounds. The CYP3A subfamily members (CYP3A4 and CYP3A5) are abundantly expressed in both the liver and small intestinal wall and both are important sites of drug-drug interactions. Erythromycin inhibits CYP3A4 in vitro by forming a metabolic intermediate complex (MIC) in human liver microsomes. Pharmacokinetic demonstrated that erythromycin modestly but significantly altered the pharmacokinetics of intravenous and oral midazolam, producing a 54% reduction in the systemic clearance and a two-fold increase in oral bioavailability of midazolam. Similarly, in-vitro experiments have shown that diltiazem inhibits CYP3A4 by forming an MIC. In-vivo studies report a modest drug-drug interaction between midazolam and diltiazem when both are given orally as a single dose whereby, diltiazem significantly increased the area under the curve and prolonged the elimination half-life of midazolam. However, the effect of the chronic administration of diltiazem on the pharmacokinetics of midazolam is unknown. Moreover, the effects of combining two modest inhibitors on pharmacokinetics of CYP3A substrates are unknown despite the fact that such combinations are commonplace in contemporary pharmacotherapy. Importantly the effects of combinations of inhibitors may be complex and not readily predicted from binary drug-drug interaction studies. To this end, we want to study the effect of erythromycin and diltiazem, alone and in combination, on midazolam pharmacokinetics.