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 us ed to treat ventricular arrhythmias. In vivo experiments have demonstr ated it is predominantly metabolized by the liver with <10% excreted a s unchanged drug. The major mammalian metabolites have been identified as p-hydroxymexiletine (PHM) and hydroxymethylmexiletine (HMM). The p urpose of our study was to determine whether the fungus Cunninghamella echinulata, which possesses a cytochrome P450 system analogous to tha t found in humans, could be used as a suitable in vitro model for stud ying the oxidative metabolism of rac-mexiletine. To accomplish this, a high performance liquid chromatographic assay was used that was capab le of simultaneously quantifying the enantiomers of mexiletine, HMM, a nd PHM. Utilizing this procedure, it was demonstrated that C. echinula ta stereoselectively converted rac-mexiletine into HMM (4% of added dr ug) and PHM (32% of added drug) after an incubation period of 50 hr. I n addition, metabolite biosynthesis could be optimized by altering fer mentation media components. Seven media values and seven pH values wer e evaluated. It was determined that a medium at pH 7.0 containing yeas t extract and sucrose yielded optimal amounts of metabolites.