Significant interaction between the nonprescription antihistamine diphenhydramine and the CYP2D6 substrate metoprolol in healthy men with high or lowCYP2D6 activity

The prototype "classic" over-the-counter antihistamine diphenhydramine was shown to interact with the polymorphic P450 enzyme CYP2D6. This project was undertaken to investigate (1) whether diphenhydramine inhibits the biotran sformation of the clinically relevant CYP2D6 substrate metoprolol in vitro and (2) whether this in vitro interaction results in a clinically significa nt pharmacokinetic and pharmacodynamic drug interaction in vivo. In vitro i ncubations were carried out with microsomes obtained from lymphoblastic cel ls transfected with CYP2D6 complementary deoxyribonucleic acid to determine the type and extent of inhibition, We then randomized 16 subjects with gen etically determined high. (extensive metabolizers) or low (poor metabotizer s) CYP2D6 activity to receive metoprolol (100 mg) in the presence of steady -state concentrations of diphenhydramine or placebo, In vitro, diphenhydram ine was a potent competitive inhibitor of metoprolol alpha-hydroxylation, e xhibiting an inhibitory constant of 2 mu mol/L and increasing the Michaelis -Menten constant of metoprolol sixfold, In vivo, diphenhydramine decreased metoprolol oral and nonrenal clearances twofold and metoprolol-->alpha-hydr oxymetoprolol partial metabolic clearance 2.5-fold in extensive metabolizer s (all P <.05) but not in poor metabolizers (P >.2). Although the hemodynam ic response to metoprolol was unaltered by diphenhydramine in poor metaboli zers (P>.05), metoprolol-related effects on heart rate, systolic blood pres sure, and Doppler-derived aortic blood flow peak velocity were more pronoun ced and fasted significantly longer in extensive metabolizers receiving dip henhydramine compared with poor metabolizers and extensive metabolizers rec eiving placebo. We conclude that diphenhydramine inhibits the metabolism of metoprolol in extensive metabolizers, thereby prolonging the negative chro notropic and inotropic effects of the drug. Clinically relevant drug intera ctions may occur between diphenhydramine and many CYP2D6 substrates, partic ularly those with a narrow therapeutic index.