The effects of a synthetic diet on the pharmacokinetics of ethyl methyl sulphide and its sulphoxide and sulphone metabolites in rats

Ethyl methyl sulphide (EMS) is a simple dialkyl sulphide, which occurs natu rally and forms part structures of more complex drug molecules. EMS is oxid ized to the corresponding sulphoxide (EMSO) and sulphone (EMSO2) derivative s both in vitro and in vivo. Two distinct enzymatic pathways appear to be i nvolved in this sulphoxidation process; the flavin-containing monooxygenase (FMO) is largely responsible for the S-oxidation of EMS to its sulphoxide while both cytochrome P-450 and FMO are involved in the further oxidation o f the sulphoxide to the sulphone. The pharmacokinetics of EMS and its sulph oxide and sulphone metabolites were examined in male wistar rats placed on normal rat chow and those placed on a synthetic diet. Blood levels of EMS w ere analysed by a sensitive headspace gas chromatographic assay. A separate gas chromatographic assay was developed to monitor the blood levels of EMS O and EMSO2. The pharmacokinetics of EMS in control rats were linear from 1 0 to 40 mg/kg dose range. The blood concentration-time profile of EMS decli ned monoexponentially. EMS was rapidly eliminated from rat blood with a ter minal half-life of 0.14 h and was not detectable 1 h After administration. Following intravenous administration of EMSO (5 mg/kg), the blood concentra tion-time profile of EMSO declined with a terminal half-life (t(1/2)) of 1. 46 h, about ten times longer than that of the parent sulphide. After admini stration of EMSO2 (15 mg/kg), the sulphone was metabolically stable and was eliminated very slowly from the blood. The in vivo disposition of EMS and EMSO were clearly altered in rats maintained on a synthetic diet following administration of EMS or EMSO. The pharmacokinetic data were consistent wit h a diminished drug oxidising capacity in rats placed on the synthetic diet and could serve as a useful probe for monitoring the regulation of FMO in animals.