METABOLIC INTESTINAL DRUG INTERACTIONS

这项拨款提案中描述的研究的长期目标是 了解抑制药物相互作用的机制基础 涉及人类细胞色素P3A4。这是重要的，以避免不利的 当今临床上使用的许多药物的事件，这些药物要么是 酶的底物或抑制物。它还将极大地帮助 预测新分子实体的体内抑制潜能 正在开发中。我们假设几个临床上重要的 抑制药物对细胞色素P3A底物的一次通过清除 主要是肠粘膜，它们可以持续很长时间 缓蚀剂吸收的时间。这一点将与 以下是具体目标： 一、确定唑类抗真菌药物是否具有抗真菌作用 细胞色素P3A标志物咪达唑仑发生首过代谢 主要是在肠粘膜而不是肝脏内，以及 这种优先抑制将持续到缓蚀期以后。 由于抑制物在粘膜中的隔离而被吸收。 II.确定肠道而不是肝脏的抑制 首过是二烷胺类抑制剂的主要作用机制 提高口服咪达唑仑的系统利用度， 确定抑制的时间进程是否平行于 一种缓慢可逆的MI-CyP3A复合体。 确定多次服用阿司匹林的体内效应 大环内酯类药物的原型，口服咪达唑仑的红霉素 生物利用度，取决于CYP3A4在体内表达的量 肠粘膜和二脱甲基随时间的积累 红霉素在那个组织中的代谢物。 我们将采用三种实验范式；药代动力学研究 健康人体志愿者；人体来源的体外代谢研究 Caco-2细胞培养单层和体内肠道提取研究 在一个家养猪模型中。这种三层方法应该允许我们 确定易于预测、可逆的相互作用的贡献 缓蚀剂和底物之间，以及电流的不可预测，缓慢地 细胞内抑制物隔离和心肌梗死等可逆现象 复杂的队形。

The long-term goal of the research described in this grant proposal is to understand the mechanistic basis for inhibitory drug interactions involving human CYP3A4. This is important for the avoidance of adverse events with the numerous drugs in clinical use today that are either a substrate or inhibitor of the enzyme. It will also aid greatly in predicting the in vivo inhibitory potential for new molecular entities under develop. We hypothesize that effects of several clinically important inhibitory drugs on the first-pass clearance of CYP3A substrate occurs predominantly with the intestinal mucosa, and they can last well beyond the period of inhibitor absorption. This will be investigated with the following Specific Aims: I. To determine whether the inhibitory effect of azole anti-fungals on the first-pass metabolism of the CYP3A marker midazolam occurs predominantly within the intestinal mucosa rather than liver, and whether this preferential inhibition persists will beyond the period of inhibitor absorption due to sequestration of inhibitor in the mucosa. II. To determine whether inhibition of intestinal rather than hepatic first-pass is the predominant mechanism by which dialkylamine inhibitors elevate the systemic availability of orally administered midazolam, and to determine whether the time-course of inhibition parallels the formation of a slowly reversible MI-CYP3A complex. III. To determine if the in vivo effect during multiple dosing of a prototype macrolide inhibitor, erythromycin, an oral midazolam bioavailability, depends on the amount of CYP3A4 expressed in the intestinal mucosa and the accumulation over time of the di-desmethyl erythromycin metabolite in that tissue. We will employ three experimental paradigms; pharmacokinetic studies in healthy human volunteers; in vitro metabolic studies in human-derived Caco-2 cell culture monolayers; and in vivo intestinal extraction studies in a domestic pig model. This three-tiered approach should allow us to identify the contribution of readily predictable, reversible interactions between inhibitor and substrate, and current unpredictable, slowly reversible phenomena such as intracellular inhibitor sequestration and MI complex formation.