Abstract
Classic antihistamines, namely diphenhydramine, chlorpheniramine, clemastine, perphenazine, hydroxyzine, and tripelennamine, share structural features with substrates and inhibitors of the polymorphic cytochrome P450 (CYP) isozyme CYP2D6. Therefore, the current study was undertaken to characterize the in vitro inhibition of CYP2D6 by these commonly used, histamine H1receptor antagonists. Microsomal incubations were performed using bufuralol as a specific CYP2D6 substrate and microsomes derived from human cells transfected with CYP2D6 cDNA. Reaction velocities were assessed in the absence and presence of antihistamines (20 μM) at 11 substrate concentrations (1, 2.5, 5, 7.5, 10, 15, 20, 25, 50, 75, and 100 μM), as well as at three nonsaturating substrate concentrations (2.5, 5, and 20 μM) and three inhibitor concentrations (5, 20, and 50 μM). In the presence of all antihistamines, theVmax and KM of bufuralol 1′-hydroxylation were significantly altered, compared with the uninhibited reaction (p < 0.05). Lineweaver-Burke plots suggested competitive inhibition of the reaction by diphenhydramine and mixed inhibition by all other antihistamines tested. Diphenhydramine and chlorpheniramine, with estimatedKi values of ∼11 μM, were the weakest inhibitors of CYP2D6 in vitro. Whereas tripelennamine, promethazine, and hydroxyzine were similar in their inhibitory capacities (Ki ∼ 4–6 μM), clemastine appeared to be significantly more potent, with aKi of ∼2 μM. These data demonstrate that classic histamine H1 receptor antagonists, available in over-the-counter preparations, inhibit CYP2D6 in vitro. Furthermore, the CYP2D6-inhibitory concentrations of these antihistamines are in the range of their expected hepatic blood concentrations, suggesting that, under specific circumstances, clinically relevant interactions between classic antihistamines and CYP2D6 substrates might occur.
Footnotes
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Send reprint requests to: Bettina A. Hamelin, Pharm.D., Centre de Recherche, Hôpital Laval, 2725, Chemin Ste-Foy, Ste-Foy, Québec, Canada G1V 4G5.
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This work was supported by Medical Research Council Grants MT-13263 and MT-11876. B.A.H. is the recipient of a scholarship from the Fonds de la Recherche en Santé du Québec, A.B. is the recipient of a scholarship from the Quebec Heart Institute, B.D. is the recipient of a studentship from the Fonds pour la Formation de Chercheurs et l’Aide à la Recherche and a Merck Frosst award, and J.T. is the recipient of a scholarship from the Joseph Edwards Foundation. This work was presented in part at the Annual Meeting of the American Society of Clinical Pharmacology and Therapeutics, Orlando, FL, March 1996, and at the Annual Meeting of the American College of Clinical Pharmacy, Nashville, TN, August 1996.
- Abbreviation used is::
- P450 or CYP
- cytochrome P450
- Received June 27, 1997.
- Accepted February 17, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
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