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 naturally and forms part structures of more complex drug molecules. EMS is oxidized to the corresponding sulphoxide (EMSO) and sulphone (EMSO2) derivatives both in vitro and in vivo. Two distinct enzymatic pathways appear to be involved in this sulphoxidation process; the flavin-containing monooxygenase (FMO) is largely responsible for the S-oxidation of EMS to its sulphoxide while both cytochrome P450 and FMO are involved in the further oxidation of the sulphoxide to the sulphone. The pharmacokinetics of EMS and its sulphoxide 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 were analysed by a sensitive headspace gas chromatographic assay. A separate gas chromatographic assay was developed to monitor the blood levels of EMSO and EMSO2. The pharmacokinetics of EMS in control rats were linear from 10 to 40 mg/kg dose range. The blood concentration-time profile of EMS declined monoexponentially. EMS was rapidly eliminated from rat blood with a terminal half-life of 0.14 h and was not dytectable 1 h after administration. Following intravenous administration of EMSO (5 mg/kg), the blood concentration-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 administration 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 with 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.
Nnane
L P
LP
Department of Pharmacy, King's College London, UK.
Damani
L A
LA
Hutt
A J
AJ
D000818:Animals; D002849:Chromatography, Gas; D005526:Food, Formulated; D007275:Injections, Intravenous; D008297:Male; D008995:Monoamine Oxidase / Q000378:metabolism; D010084:Oxidation-Reduction; D051381:Rats; D017208:Rats, Wistar; D013440:Sulfides / Q000493:pharmacokinetics*; D013450:Sulfones / Q000378:metabolism; D013454:Sulfoxides / Q000378:metabolism
D013440:Sulfides; D013450:Sulfones; D013454:Sulfoxides; C403226:ethylmethyl sulfide; D008995:Monoamine Oxidase