Abstract
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 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.
Footnotes
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Send reprint requests to: Dr. Franco M. Pasutto, Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada T6G 2N8.
- Abbreviations used are::
- PHM
- p-hydroxymexiletine
- HMM
- hydroxymethylmexiletine
- EM
- extensive metabolizer
- PM
- poor metabolizer
- NEIC
- S-(+)-1-(1-naphthyl)ethyl isocyanate
- UAMH
- University of Alberta Microfungus Collection and Herbarium
- ATCC
- American Type Culture Collection
- Received September 12, 1996.
- Accepted January 28, 1997.
- The American Society for Pharmacology and Experimental Therapeutics
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