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Preferential inhibition of CYP1A enzymes in hepatic microsomes by mexiletine

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Summary

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 β-naphthoflavone (β-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 μM and 8.3 μM, 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 μM) 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 β-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.

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Authors and Affiliations

  1. Hospital Pharmacy Department, Shiga University of Medical Science, 520-2192, Seta, Ohtsu, Japan

    H. Konishi, K. Morita, T. Minouchi & A. Yamaji

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  1. H. Konishi
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  2. K. Morita
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  3. T. Minouchi
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  4. A. Yamaji
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Konishi, H., Morita, K., Minouchi, T. et al. Preferential inhibition of CYP1A enzymes in hepatic microsomes by mexiletine. Eur. J. Drug Metab. Pharmacokinet. 24, 149–153 (1999). https://doi.org/10.1007/BF03190360

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  • DOI: https://doi.org/10.1007/BF03190360

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