RT Journal Article
SR Electronic
T1 <em>In Vitro</em> Characterization of Cytochrome P450 2D6 Inhibition by Classic Histamine H<sub>1</sub> Receptor Antagonists
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 536
OP 539
VO 26
IS 6
A1 Hamelin, Bettina A.
A1 Bouayad, Asmàa
A1 Drolet, Benoît
A1 Gravel, Anne
A1 Turgeon, Jacques
YR 1998
UL http://dmd.aspetjournals.org/content/26/6/536.abstract
AB 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 &lt; 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. The American Society for Pharmacology and Experimental Therapeutics