Toward optimal treatment in women

The effect of sex on metoprolol-diphenhydramine interaction

Ashish Sharma, Philippe Pibarot, Sylvie Pilote, Jean G. Dumesnil, Marie Arsenault, Pierre Maxime Bélanger, Bernd Meibohm, Bettina A. Hamelin

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

The objective of this study was to determine if sex influences the pharmacokinetics and hemodynamics of the CYP2D6 substrate metoprolol and its interaction with diphenhydramine (CYP2D6 inhibitor) in healthy young participants with high (extensive metabolizer [EM]) or low (poor metabolizer [PM]) CYP2D6 activities. A prespecified comparative analysis of data from 2 sequential clinical trials that included 16 EM and 4 PM women and 10 EM and 6 PM men was performed. The participants in the 2 trials were administered a single oral dose of 100 mg metoprolol in the presence of steady-state diphenhydramine or placebo. Serial plasma and urine samples were obtained for 48 hours, and hemodynamic data was obtained for 12 hours after metoprolol. In the placebo arm, EM and PM women had 62% and 59% higher S-metoprolol AUC 0- 0-∞ and 26% and 71% lower CL/F, respectively, compared to men with the same phenotype (all Ps <.05 women compared to men). These differences dissipated on body weight (WT) correction. Women (especially PMs) experienced greater negative chronotropic effects of metoprolol than men (P <.0001 women compared to men). Diphenhydramine coadministration increased S-metoprolol AUC by 84% in EM women and 45% in EM men (P <.009 women compared to men). In the diphenhydramine arm, sex differences in pharmacokinetics persisted even after WT correction, resulting in greater negative chronotropic effects in women (all Ps <.05 women compared to men). Metoprolol dose should be adjusted for body weight, particularly in women. Coadministration of a CYP2D6 inhibitor such as diphenhydramine, by a patient at similar doses in the 2 sexes, could result in a greater inhibition of clearance of CYP2D6 substrates with a resulting higher risk of pronounced pharmacological and adverse effects in women compared to men.

Original languageEnglish (US)
Pages (from-to)214-225
Number of pages12
JournalJournal of clinical pharmacology
Volume50
Issue number2
DOIs
StatePublished - Feb 1 2010

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Diphenhydramine
Metoprolol
Cytochrome P-450 CYP2D6
Therapeutics
Area Under Curve
Pharmacokinetics
Hemodynamics
Placebos
Body Weight
Sex Characteristics
Healthy Volunteers
Clinical Trials
Urine
Pharmacology

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Pharmacology (medical)

Cite this

Sharma, A., Pibarot, P., Pilote, S., Dumesnil, J. G., Arsenault, M., Maxime Bélanger, P., ... Hamelin, B. A. (2010). Toward optimal treatment in women: The effect of sex on metoprolol-diphenhydramine interaction. Journal of clinical pharmacology, 50(2), 214-225. https://doi.org/10.1177/0091270009340417

Toward optimal treatment in women : The effect of sex on metoprolol-diphenhydramine interaction. / Sharma, Ashish; Pibarot, Philippe; Pilote, Sylvie; Dumesnil, Jean G.; Arsenault, Marie; Maxime Bélanger, Pierre; Meibohm, Bernd; Hamelin, Bettina A.

In: Journal of clinical pharmacology, Vol. 50, No. 2, 01.02.2010, p. 214-225.

Research output: Contribution to journalArticle

Sharma, A, Pibarot, P, Pilote, S, Dumesnil, JG, Arsenault, M, Maxime Bélanger, P, Meibohm, B & Hamelin, BA 2010, 'Toward optimal treatment in women: The effect of sex on metoprolol-diphenhydramine interaction', Journal of clinical pharmacology, vol. 50, no. 2, pp. 214-225. https://doi.org/10.1177/0091270009340417
Sharma A, Pibarot P, Pilote S, Dumesnil JG, Arsenault M, Maxime Bélanger P et al. Toward optimal treatment in women: The effect of sex on metoprolol-diphenhydramine interaction. Journal of clinical pharmacology. 2010 Feb 1;50(2):214-225. https://doi.org/10.1177/0091270009340417
Sharma, Ashish ; Pibarot, Philippe ; Pilote, Sylvie ; Dumesnil, Jean G. ; Arsenault, Marie ; Maxime Bélanger, Pierre ; Meibohm, Bernd ; Hamelin, Bettina A. / Toward optimal treatment in women : The effect of sex on metoprolol-diphenhydramine interaction. In: Journal of clinical pharmacology. 2010 ; Vol. 50, No. 2. pp. 214-225.
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