title: Mexiletine metabolism in vitro by human liver.
abstract: 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.
authors.affiliation: Laboratoire de Pharmacologie, Faculté de Médecine de Lille, France.
authors.forename: F
authors.initials: F
authors.lastname: Broly
authors.forename: C
authors.initials: C
authors.lastname: Libersa
authors.forename: M
authors.initials: M
authors.lastname: Lhermitte
mesh_terms: D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D006801:Humans; D006900:Hydroxylation; D066298:In Vitro Techniques; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D008801:Mexiletine / Q000031:analogs & derivatives / Q000378:metabolism* / Q000493:pharmacokinetics; D013347:Subcellular Fractions / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism
chemical_list: D008801:Mexiletine; C045807:6-hydroxymethylmexiletine; C045808:4-hydroxymexiletine; D003577:Cytochrome P-450 Enzyme System