Potential of hydroxyebastine and terfenadine alcohol to inhibit the human cytochrome P450 2J2 isoform

Although selective inhibitors of cytochrome P450 enzymes can be used to determine relative contributions of the enzymes to xenobiotic metabolism, characterization of CYP2J2 in drug metabolism is more challenging due to lack of selective, well-characterized inhibitors. Thus, selectivity of hydroxyebastine, which has high affinity for recombinant CYP2J2, was studied. The IC50 value of hydroxyebastine in CYP2J2-mediated astemizole O-demethylation activity was lower than that of its structural analog, terfenadine alcohol. Terfenadine alcohol inhibited several other P450 activities, such as CYP2D6, more potently than CYP2J2, and is thus not suitable as a CYP2J2-selective inhibitor. Inhibitory potential values of hydroxyebastine in CYP2J2-catalyzed astemizole O-demethylation, tolbutamide hydroxylation (CYP2C9), S-mephenytoin hydroxylation (CYP2C19), and dextromethorphan O-demethylation (CYP2D6) were 0.45, 2.74, 10.22, and 3.83 μM, respectively. The inhibitory potential of other P450 enzymes, such as CYP1A2, CYP2B6, CYP2E1, and CYP3A, was negligible. Although hydroxyebastine was a relatively potent inhibitor of CYP2J2, it provided a selectivity of only > 6-fold (CYP2J2 vs. other P450s). However, hydroxyebastine can serve as a relatively selective inhibitor of CYP2J2 and can be used to characterize the contribution of CYP2J2 to xenobiotic metabolism due to the lack of a more specific inhibitor.