Suitability of lingual venous blood to determine the acid-base and blood gas status of dogs under anesthesia

Pre-print file deposited according to publisher conditions in SHERPA/RoMEO, January 4, 2011.Ye

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