METABOLIC INTESTINAL DRUG INTERACTIONS

这项研究的长期目标是 了解抑制性药物相互作用的机制基础 涉及人CYP 3A 4。这对于避免不利的 今天临床使用的许多药物的事件， 酶的底物或抑制剂。它也将大大有助于 预测新分子实体的体内抑制潜力 欠发达。我们假设几种临床上重要的 抑制药物对CYP 3A底物的首过清除率 主要是与肠粘膜，他们可以持续很长时间， 抑制剂吸收期。这将与调查 具体目标： I.为了确定唑类抗真菌药对 发生CYP 3A标志物咪达唑仑的首过代谢 主要在肠粘膜而不是肝脏内，以及是否 这种优先抑制作用将持续到抑制剂作用期之后 由于抑制剂在粘膜中的隔离而导致吸收。 二. 为了确定是否抑制肠而不是肝 首过是二烷基胺抑制剂 提高口服咪达唑仑的全身利用度， 确定抑制的时间过程是否与 缓慢可逆的MI-CYP 3A复合物。 三.为了确定在多次给药期间， 原型大环内酯抑制剂，红霉素，口服咪达唑仑 生物利用度，取决于CYP 3A 4在细胞中表达的量。 肠粘膜和积累随着时间的推移， 组织中红霉素代谢物。 我们将采用三种实验范式： 健康人类志愿者;人源性体外代谢研究 Caco-2细胞培养单层;和体内肠浸提研究 在家猪模型中。这三个层次的方法应使我们能够 确定容易预测的、可逆的相互作用的贡献 在抑制剂和底物之间，电流不可预测， 可逆现象，如细胞内抑制剂螯合和MI 复杂的形成。

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.