Significant interaction between the nonprescription antihistamine diphenhydramine and the CYP2D6 substrate metoprolol in healthy men with high or low CYP2D6 activity.

摘要: The prototype "classic" over-the-counter antihistamine diphenhydramine was shown to interact with the polymorphic P450 enzyme CYP2D6. This project undertaken investigate (1) whether inhibits biotransformation of clinically relevant CYP2D6 substrate metoprolol in vitro and (2) this interaction results a significant pharmacokinetic pharmacodynamic drug vivo. In incubations were carried out microsomes obtained from lymphoblastic cells transfected complementary deoxyribonucleic acid determine type extent inhibition. We then randomized 16 subjects genetically determined high (extensive metabolizers) or low (poor activity receive (100 mg) presence steady-state concentrations placebo. vitro, potent competitive inhibitor alpha-hydroxylation, exhibiting an inhibitory constant 2 micromol/L increasing Michaelis-Menten sixfold. vivo, decreased oral nonrenal clearances twofold metoprolol-->alpha-hydroxymetoprolol partial metabolic clearance 2.5-fold extensive metabolizers (all P .2). Although hemodynamic response unaltered by poor (P > .05), metoprolol-related effects on heart rate, systolic blood pressure, Doppler-derived aortic flow peak velocity more pronounced lasted significantly longer receiving compared conclude that metabolism metabolizers, thereby prolonging negative chronotropic inotropic drug. Clinically interactions may occur between many substrates, particularly those narrow therapeutic index.