title: The stereoselective biotransformation of the anti-obesity drug sibutramine in rat liver microsomes and in primary cultures of rat hepatocytes.
abstract: Sibutramine is an anti-obesity drug sold as a racemic mixture under the trademark Meridia or Reductil. With the aim of evaluating the stereoselectivity in phase I of sibutramine biotransformation, the formation of the main metabolites from R -sibutramine, S -sibutramine and rac-sibutramine was studied in rat microsomes and primary cultures of hepatocytes. A novel analytical method for the determination of sibutramine and its phase I metabolites in culture medium and microsomal incubates using isocratic reversed-phase liquid chromatography with UV detection was developed. Only two metabolites, mono-desmethylsibutramine (M1) and di-desmethylsibutramine (M2), were found in the rat microsomes incubated with sibutramine and NADPH. The kinetics of M1 and M2 formation slightly differed depending on the enantiomeric form of the sibutramine used. The stereoselectivity in sibutramine biotransformation was much more evident in primary cultures of rat hepatocytes. While R-sibutramine incubation led to the formation of M1 and M2 metabolites only, the incubation of S-sibutramine or rac-sibutramine (to a lesser extent) resulted in four major metabolites (M1, M2, M3 and M4) and 2 or 3 minor metabolites. On the basis of our results, R-sibutramine might represent the more advantageous sibutramine enantiomer from the pharmacokinetic standpoint.
authors.affiliation: Department of Biochemical Sciences, Research Centre LN00B125, Faculty of Pharmacy, Charles University, Heyrovského 1203, CZ 50005 Hradec Králové, Czech Republic.
authors.forename: Marek
authors.initials: M
authors.lastname: Link
authors.forename: Romana
authors.initials: R
authors.lastname: Novotná
authors.forename: Bohumila
authors.initials: B
authors.lastname: Suchanová
authors.forename: Lenka
authors.initials: L
authors.lastname: Skálová
authors.forename: Vladimír
authors.initials: V
authors.lastname: Wsól
authors.forename: Barbora
authors.initials: B
authors.lastname: Szotáková
mesh_terms: D000818:Animals; D001067:Appetite Depressants / Q000737:chemistry / Q000493:pharmacokinetics*; D001711:Biotransformation; D018929:Cell Culture Techniques; D002470:Cell Survival / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D003503:Cyclobutanes / Q000737:chemistry / Q000493:pharmacokinetics*; D022781:Hepatocytes / Q000378:metabolism*; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D009249:NADP / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013237:Stereoisomerism
chemical_list: D001067:Appetite Depressants; D003503:Cyclobutanes; D009249:NADP; C058254:sibutramine