This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor 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.
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