TY - JOUR T1 - Stereoselective Metabolism of <em>rac</em>-Mexiletine by the Fungus <em>Cunninghamella echinulata</em> Yields the Major Human Metabolites Hydroxymethylmexiletine and<em>p</em>-Hydroxymexiletine JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 685 LP - 692 VL - 25 IS - 6 AU - D. G. Freitag AU - R. T. Foster AU - R. T. Coutts AU - M. A. Pickard AU - F. M. Pasutto Y1 - 1997/06/01 UR - http://dmd.aspetjournals.org/content/25/6/685.abstract N2 - rac-Mexiletine is an orally effective class 1b antiarrhythmic agent used to treat ventricular arrhythmias. In vivo experiments have demonstrated it is predominantly metabolized by the liver with &lt;10% excreted as unchanged drug. The major mammalian metabolites have been identified asp-hydroxymexiletine (PHM) and hydroxymethylmexiletine (HMM). The purpose of our study was to determine whether the fungusCunninghamella echinulata, which possesses a cytochrome P450 system analogous to that found in humans, could be used as a suitablein vitro model for studying the oxidative metabolism ofrac-mexiletine. To accomplish this, a high performance liquid chromatographic assay was used that was capable of simultaneously quantifying the enantiomers of mexiletine, HMM, and PHM. Utilizing this procedure, it was demonstrated that C. echinulata stereoselectively converted rac-mexiletine into HMM (4% of added drug) and PHM (32% of added drug) after an incubation period of 50 hr. In addition, metabolite biosynthesis could be optimized by altering fermentation media components. Seven media values and seven pH values were evaluated. It was determined that a medium at pH 7.0 containing yeast extract and sucrose yielded optimal amounts of metabolites. The American Society for Pharmacology and Experimental Therapeutics ER -