Preferential inhibition of CYP1A enzymes in hepatic microsomes by mexiletine.

We examined the inhibitory behavior of theophylline oxidations and a variety of cytochrome P450 (P450)-dependent metabolism in the presence of mexiletine (MEX), using hepatic microsomes from both control mice and mice exposed to beta-naphthoflavone (beta-NF). Theophylline metabolism, which is mainly catalyzed by CYP1A2, was susceptible to competitive inhibition by MEX. The calculated inhibition constants (Ki) for theophylline 3-demethylation and its 8-hydroxylation were 4.3 microM and 8.3 microM, respectively, which are comparable to the recommended therapeutic serum range for MEX. The inhibitory potency of MEX on cytochrome P450-dependent enzyme activities diverged among the several metabolic reactions, which were probes for CYP1A, 2A, 2C, 2D, 2E and 3A subfamilies. The Ki value (6.7 microM) for methoxyresorufin O-demethylation mediated by CYP1A2 agreed with those from theophylline oxidations. These metabolic reactions exhibited the smallest Ki values, 1-3 orders of magnitude lower than activities of other constitutive cytochrome P450 species. Similar degrees of inhibition were observed in CYP1A1, a beta-NF-inducible isoform with a relatively high conformity to CYP1A2. These results indicate that MEX acts as a selective and potent inhibitor of the CYP1A enzymes responsible for oxidative biotransformation of chemicals such as theophylline. This evidence provides a fundamental explanation for the pharmacokinetic interactions experienced in clinical practice.