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KMID : 0043320100330020267
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Archives of Pharmacal Research
2010 Volume.33 No. 2 p.267 ~ p.273
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Enantioselective Pharmacokinetics of Sibutramine in Rat
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Kang Won-Ku
Noh Keum-Han
Bae Kyoung-Jin
Min Bo-Kyoung
Kim Eun-Young
Kwon Kwang-II
Jeong Tae-Cheon
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Abstract
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Racemic sibutramine is widely used to treat obesity owing to its inhibition of serotonin and noradrenaline reuptake in synapses. Although the enantioselective effects of sibutramine and its two active desmethyl- metabolites, monodesmethylsibutramine (MDS) and didesmethylsibutramine (DDS), on anorexia and energy expenditure have been elucidated, the enantioselective pharmacokinetics of sibutramine are still unclear. Therefore, we aimed to characterize the enantioselective pharmacokinetics of sibutramine and its metabolites in plasma and urine following an intravenous and a single oral administration of sibutramine in rats. The absolute bioavailability of sibutramine was only about 7%. The pharmacologically less effective S-isomer of DDS was predominant in the plasma: the Cmax and the AUCinf were 28 and 30 times higher than those of the R-isomer, respectively (p<0.001). In the urine, the concentrations of the R-isomers of hydroxylated DDS and hydroxylated and carbamoylglucuronized MDS and DDS appeared to be 11.3-, 5.1-, and 5.3-times the concentrations of the respective S-isomers. Thus, regardless of increased potency than the S-enantiomers, the R-enantiomers of the sibutramine metabolites MDS and DDS were present at lower concentrations, owing to their rapid biotransformation to hydroxylated and/or carbamoylglucuronized forms and their faster excretion in the urine. The present study is the first to elucidate the enantioselective pharmacokinetics of sibutramine in rats.
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KEYWORD
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Enantioselective pharmacokinetics, Sibutramine, Monodesmethylsibutramine, Didesmethylsibutramine, Isomer
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