THE EFFECT OF CONCOMITANT ADMINISTRATION OF ERYTHROMYCIN AND DILTIAZEM ON CYP

该子项目是利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得主要资金， 因此可以在其他CRISP条目中表示。列出的机构是 中心，不一定是研究者的机构。 细胞色素P450 3A（CYP 3A）亚家族酶是药物代谢中最重要的酶之一，负责多种内源性和外源性化合物的代谢。 CYP 3A亚家族成员（CYP 3A 4和CYP 3A 5）在肝脏和小肠壁中大量表达，两者都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体复合物（MIC）抑制CYP 3A 4。 药代动力学表明，红霉素适度但显著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率降低54%，口服生物利用度增加2倍。同样，体外实验表明地尔硫卓通过形成MIC抑制CYP 3A 4。体内研究报告，当咪达唑仑和地尔硫卓均以单剂量口服给药时，咪达唑仑和地尔硫卓之间存在适度的药物相互作用，其中地尔硫卓显著增加了咪达唑仑的曲线下面积并延长了其消除半衰期。然而，地尔硫卓长期给药对咪达唑仑药代动力学的影响尚不清楚。 此外，联合两种适度抑制剂对CYP 3A底物药代动力学的影响尚不清楚，尽管这种联合在当代药物治疗中很常见。重要的是，抑制剂组合的作用可能是复杂的，并且不容易从二元药物相互作用研究中预测。为此，我们想研究红霉素和地尔硫卓单独和联合使用对咪达唑仑药代动力学的影响。

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.