IN-VITRO CHARACTERIZATION OF CYTOCHROME-P450 2D6 INHIBITION BY CLASSIC HISTAMINE H-1 RECEPTOR ANTAGONISTS

Classic antihistamines, namely diphenhydramine, chlorpheniramine, clem astine, perphenazine, hydroxyzine, and tripelennamine, share structura l features with substrates and inhibitors of the polymorphic cytochrom e P450 (CYP) isozyme CYP2D6. Therefore, the current study was undertak en to characterize the in vitro inhibition of CYP2D6 by these commonly used, histamine H, receptor antagonists. Microsomal incubations were performed using bufuralol as a specific CYP2D6 substrate and microsome s derived from human cells transfected with CYP2D6 cDNA. Reaction velo cities were assessed in the absence and presence of antihistamines (20 mu M) at 11 substrate concentrations (1, 2.5, 5, 7.5, 10, 15, 20, 25, 50, 75, and 100 mu M), as well as at three nonsaturating substrate co ncentrations (2.5, 5, and 20 mu M) and three inhibitor concentrations (5, 20, and 50 mu M). In the presence of all antihistamines, the V-max and K-M of bufuralol 1'-hydroxylation were significantly altered, com pared with the uninhibited reaction (p < 0.05). Lineweaver-Burke plots suggested competitive inhibition of the reaction by diphenhydramine a nd mixed inhibition by all other antihistamines tested. Diphenhydramin e and chlorpheniramine, with estimated K-i values of similar to 11 mu M, were the weakest inhibitors of CYP2D6 in vitro. Whereas tripelennam ine, promethazine, and hydroxyzine were similar in their inhibitory ca pacities (K-i similar to 4-6 mu M), clemastine appeared to be signific antly more potent, with a K-i of similar to 2 mu M. These data demonst rate that classic histamine H-1 receptor antagonists, available in ove r-the-counter preparations, inhibit CYP2D6 in vitro. Furthermore, the CYP2D6-inhibitory concentrations of these antihistamines are in the ra nge of their expected hepatic blood concentrations, suggesting that, u nder specific circumstances, clinically relevant interactions between classic antihistamines and CYP2D6 substrates might occur.