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 < .05) but not in poor metabolizers (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.

[1]  B. Drolet,et al.  Block of potassium currents in guinea pig ventricular myocytes and lengthening of cardiac repolarization in man by the histamine H1 receptor antagonist diphenhydramine. , 1999, The Journal of pharmacology and experimental therapeutics.

[2]  B. Drolet,et al.  In vitro characterization of cytochrome P450 2D6 inhibition by classic histamine H1 receptor antagonists. , 1998, Drug metabolism and disposition: the biological fate of chemicals.

[3]  A. Hoes,et al.  Increased survival with β-blockers: Importance of ancillary properties , 1997 .

[4]  L. M. Buske Clinical comparison of histamine H1–receptor antagonist drugs , 1996 .

[5]  J. Turgeon,et al.  The disposition of fluoxetine but not sertraline is altered in poor metabolizers of debrisoquin , 1996, Clinical pharmacology and therapeutics.

[6]  N. Vermeulen,et al.  A three-dimensional protein model for human cytochrome P450 2D6 based on the crystal structures of P450 101, P450 102, and P450 108. , 1996, Chemical research in toxicology.

[7]  T. Kamataki,et al.  CYP2D6 is the principal cytochrome P450 responsible for metabolism of the histamine H1 antagonist promethazine in human liver microsomes. , 1996, Pharmacogenetics (London).

[8]  O. Andreassen,et al.  Detection of the poor metabolizer-associated CYP2D6(D) gene deletion allele by long-PCR technology. , 1995, Pharmacogenetics.

[9]  D. Flockhart,et al.  Stereoselective inhibition of CYP2D6 by chlorpheniramine , 1995 .

[10]  A. Wood,et al.  Stereoselective disposition of carvedilol is determined by CYP2D6 , 1995, Clinical pharmacology and therapeutics.

[11]  M R Franz,et al.  Terfenadine Increases the QT Interval in Isolated Guinea Pig Heart , 1995, Journal of cardiovascular pharmacology.

[12]  M. Eichelbaum,et al.  Cloning and sequencing of a new non-functional CYP2D6 allele: deletion of T1795 in exon 3 generates a premature stop codon. , 1994, Pharmacogenetics.

[13]  D. Wermeling,et al.  Pharmacodynamics of Racemic and S(—)‐Atenolol in Humans , 1994, Journal of clinical pharmacology.

[14]  F. Simons,et al.  The pharmacology and use of H1-receptor-antagonist drugs. , 1994, The New England journal of medicine.

[15]  Y Chen,et al.  Mechanism of the cardiotoxic actions of terfenadine. , 1993, JAMA.

[16]  F. Simons New H1-receptor antagonists: worth the price? , 1992, Annals of allergy.

[17]  M. Harrison,et al.  Differential response of β‐adrenergic receptor—mediated heart rate and aortic blood flow acceleration to timolol , 1992, Clinical pharmacology and therapeutics.

[18]  H K Kroemer,et al.  Influence of debrisoquine phenotype and of quinidine on mexiletine disposition in man. , 1991, The Journal of pharmacology and experimental therapeutics.

[19]  G. Alván,et al.  Clinical consequences of polymorphic drug oxidation , 1991, Fundamental & clinical pharmacology.

[20]  D. Roden,et al.  Genetically determined steady-state interaction between encainide and quinidine in patients with arrhythmias. , 1990, The Journal of pharmacology and experimental therapeutics.

[21]  M. Harrison,et al.  Pharmacodynamics of propranolol on left ventricular function: Assessment by Doppler echocardiography , 1990, Clinical pharmacology and therapeutics.

[22]  M. Harrison,et al.  Influence of beta-adrenergic blockade upon hemodynamic response to exercise assessed by Doppler echocardiography. , 1990, American heart journal.

[23]  F. Simons H1-receptor antagonists: clinical pharmacology and therapeutics. , 1989, The Journal of allergy and clinical immunology.

[24]  G. Tucker,et al.  Stereoselective metabolism of metoprolol in Caucasians and Nigerians--relationship to debrisoquine oxidation phenotype. , 1989, British journal of clinical pharmacology.

[25]  R. Sebaldt,et al.  Efficient pharmacokinetic modeling of complex clinical dosing regimens: the universal elementary dosing regimen and computer algorithm EDFAST. , 1987, Journal of pharmaceutical sciences.

[26]  B. Chaitman,et al.  Effect of coronary artery disease on Doppler-derived parameters of aortic flow during upright exercise. , 1986, The American journal of cardiology.

[27]  G. Tucker,et al.  Debrisoquine polymorphism and the metabolism and action of metoprolol, timolol, propranolol and atenolol. , 1986, Xenobiotica; the fate of foreign compounds in biological systems.

[28]  L. Wann,et al.  Doppler echocardiographic measurement of flow velocity in the ascending aorta during supine and upright exercise. , 1985, British heart journal.

[29]  M. Tsuang,et al.  Idiosyncratic pharmacokinetics complicating treatment of major depression in an elderly woman. , 1985, The Journal of nervous and mental disease.

[30]  G. Tucker,et al.  Differential stereoselective metabolism of metoprolol in extensive and poor debrisoquin metabolizers , 1983, Clinical pharmacology and therapeutics.

[31]  G. Tucker,et al.  Oxidation phenotype--a major determinant of metoprolol metabolism and response. , 1982, The New England journal of medicine.

[32]  K. Swedberg,et al.  EFFECT ON MORTALITY OF METOPROLOL IN ACUTE MYOCARDIAL INFARCTION A Double-blind Randomised Trial , 1981, The Lancet.

[33]  M. Ghoneim,et al.  Diphenhydramine in Orientals and Caucasians , 1980, Clinical pharmacology and therapeutics.

[34]  C. Hignite,et al.  Correlation between plasma diphenhydramine level and sedative and antihistamine effects. , 1979, Clinical pharmacology and therapeutics.

[35]  Chiou Wl,et al.  Long half-life of chlorpheniramine. , 1979 .

[36]  G. Tucker,et al.  Determination of debrisoquine and its 4-hydroxy metabolite in biological fluids by gas chromatography with flame-ionization and nitrogen-selective detection. , 1977, Journal of chromatography.

[37]  N. Vermeulen,et al.  A refined substrate model for human cytochrome P450 2D6. , 1997, Chemical research in toxicology.

[38]  L. M. Du Buske,et al.  Clinical comparison of histamine H1-receptor antagonist drugs. , 1996, The Journal of allergy and clinical immunology.

[39]  J. Lynch,et al.  Cardiac electrophysiological actions of the histamine H1-receptor antagonists astemizole and terfenadine compared with chlorpheniramine and pyrilamine. , 1995, Circulation research.

[40]  S. Sindrup,et al.  Role of genetic polymorphism in psychopharmacology--an update. , 1993, Psychopharmacology series.

[41]  U. Meyer,et al.  Genetic polymorphism of debrisoquine oxidation: restriction fragment analysis and allele-specific amplification of mutant alleles of CYP2D6. , 1991, Methods in enzymology.

[42]  M. Harrison,et al.  Hemodynamic effects of calcium channel and beta-receptor antagonists: evaluation by Doppler echocardiography. , 1991, American heart journal.

[43]  A. S. Gross,et al.  The genetic polymorphism of debrisoquine/sparteine metabolism--clinical aspects. , 1990, Pharmacology & therapeutics.

[44]  M. Lennard Quantitative analysis of metoprolol and three of its metabolites in urine and liver microsomes by high-performance liquid chromatography. , 1985, Journal of chromatography.

[45]  W. L. Chiou,et al.  Long half-life of chlorpheniramine. , 1979, The New England journal of medicine.