Stereoselective metabolism of rac-mexiletine by the fungus Cunninghamella echinulata yields the major human metabolites hydroxymethylmexiletine and p-hydroxymexiletine.

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 ,10% excreted as unchanged drug. The major mammalian metabolites have been identified as p-hydroxymexiletine (PHM) and hydroxymethylmexiletine (HMM). The purpose of our study was to determine whether the fungus Cunninghamella echinulata, which possesses a cytochrome P450 system analogous to that found in humans, could be used as a suitable in vitro model for studying the oxidative metabolism of rac-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. rac-Mexiletine is a class 1b antiarrhythmic drug, similar in structure to lidocaine, used in the treatment of acute and long-term ventricular arrhythmias. Unlike lidocaine (t1/2 1.2‐1.9 hr), mexiletine is an orally effective agent with a half-life ranging from 6 to 12 hr (1). When administered to healthy volunteers, it is almost completely absorbed (88% bioavailability), with peak plasma concentrations occurring within 2‐ 4 hr (2). In coronary artery disease patients, these numbers are lower due to decreased gastric emptying (3). Mexiletine is a weakly basic drug (pKa 5 8.75) with a narrow therapeutic range. Serum concentrations must remain between 0.8 and 2.0 mg/liter, and levels .2.0 mg/liter can cause neurological side effects (4). Another feature that distinguishes mexiletine from lidocaine is that it possesses a chiral center and is administered as a racemate. Significant differences for the enantiomers have not been reported with respect to the absorption rate constant, peak plasma concentration, nor the time required to achieve peak plasma concentrations (5). However, there are reported differences in serum protein binding (6), receptor binding (7), electrophysiology (8), excretion (9), and metabolism (10) for the