DMD Celsis microsomes equal better data

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Mexiletine metabolism in vitro by human liver

F Broly, C Libersa and M Lhermitte

Laboratoire de Pharmacologie, Faculte de Medecine de Lille, France.

Human livers were used in investigations of mexiletine biotransformation in vitro. The major metabolic pathways of mexiletine oxidation, to form hydroxymethylmexiletine (HMM) and p- hydroxymexiletine (PHM), were characterized in liver cell preparations. The localization of reactions in the microsomal fraction, their heat lability, NADPH requirement and inhibition by prototype cytochrome P- 450 (P-450) inhibitors (CO, SKF 525-A, metyrapone and quinidine) implied that they were catalyzed by P-450. Kinetic studies of reactions were performed in microsomes from five different livers. Eadie-Hofstee plots of data gave no indication of systematic deviation from linearity, suggesting that over the range of mexiletine concentrations examined (3.3-133.3 microM), HMM and PHM were formed by a single enzymatic site. Within a liver preparation, Km and Vmax values for HMM and PHM formation were similar. Between livers, Km values of reactions were similar with only a 1.8-fold range for each reaction, whereas Vmax values showed 7.2- and 7.8-fold ranges for HMM and PHM production, respectively. There was a very strong correlation between Vmax values for both reactions. These results, coupled with a parallel effect of inhibitors (SKF-525A, metyrapone, alpha-naphtoflavone and quinidine) on HMM and PHM formation, argue that both reactions are mediated by a common P-450 or closely related isozymes. In addition, the present in vitro results support the hypothesis that the genetically variable P- 450 db 1 isozyme catalyzes the oxidation of mexiletine.

Volume 18, Issue 3, pp. 362-368, 05/01/1990
Copyright © 1990 by American Society for Pharmacology and Experimental Therapeutics




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D. G. Freitag, R. T. Foster, R. T. Coutts, M. A. Pickard, and F. M. Pasutto
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Drug Metab. Dispos., June 1, 1997; 25(6): 685 - 692.
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Copyright © 1990 by the American Society for Pharmacology and Experimental Therapeutics.