Abstract
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 C max and the AUC inf 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.
Similar content being viewed by others
References
Bae, K., Noh, K., Jang, K., Kim, S., Yong, C.S., Choi, H. G., Kang, J.S., Chen, J., Ma, E., Lee M., Shin, B. S., Kwon, K. I., and Kang, W., Analysis of enantiomers of sibutramine and its metabolites in rat plasma by liquid chromatography-mass spectrometry using a chiral stationaryphase column. J. Pharm. Biomed. Anal., 50, 267–270 (2009).
Bae, S. K., Cao, S., Seo, K. A., Kim, H., Kim, M. J., Shon, J. H., Liu, K. H., Zhou, H. H., and Shin, J. G., Cytochrome P450 2B6 catalyzes the formation of pharmacologically active sibutramine (N-{1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutyl}-N,N-dimethylamine) metabolites in human liver microsomes. Drug Metab. Dispos., 36, 1679–1688 (2008).
Fang, Q. K., Senanayake, C. H., Han, Z., Morency, C., Grover, P., Malone, R. E., Bulter, H., Wald, S. A., and Cameron, T. S., First preparation of enantiomerically pure sibutramine and its major metabolite, and determination of their absolute configuration by single crystal X-ray analysis. Tetrahedron Asymmetry, 10, 4477–4480 (1999).
Glick, S. D., Haskew, R. E., Maisonneuve, I. M., Carlson, J. N., and Jerussi, T. P., Enantioselective behavioral effects of sibutramine metabolites. Eur. J. Pharmacol., 397, 93–102 (2000).
Hakala, K. S., Link, M., Szotakova, B., Skalova, L., Kostiainen, R., and Ketola, R. A., Characterization of metabolites of sibutramine in primary cultures of rat hepatocytes by liquid chromatography-ion trap mass spectrometry. Anal. Bioanal. Chem., 393, 1327–1336(2009).
Link, M., Hakala, K. S., Wsol, V., Kostiainen, R., and Ketola, R. A., Metabolite profile of sibutramine in human urine: a liquid chromatography-electrospray ionization mass spectrometric study. J. Mass Spectrom., 41, 1171–1178 (2006).
Link, M., Novotná, R., Suchanová, B., Skálová, L., Wsól, V., and Szotáková, B., The stereoselective biotransformation of the anti-obesity drug sibutramine in rat liver microsomes and in primary cultures of rat hepatocytes. J. Pharm. Pharmacol., 57, 405–410 (2005).
Luscombe, G. P., Hopcroft, R. H., Thomas, P. C., and Buckett, W. R., The contribution of metabolites to the rapid and potent down-regulation of rat cortical beta-adrenoceptors by the putative antidepressant sibutramine hydrochloride. Neuropharmacology, 28, 129–134 (1989).
Luque, C. A. and Rey, J. A., Sibutramine: a serotonin-norepinephrine reuptake-inhibitor for the treatment of obesity. Ann. Pharmacother., 33, 968–977 (1999).
Author information
Authors and Affiliations
Corresponding authors
Rights and permissions
About this article
Cite this article
Noh, K., Bae, K., Min, B. et al. Enantioselective pharmacokinetics of sibutramine in rat. Arch. Pharm. Res. 33, 267–273 (2010). https://doi.org/10.1007/s12272-010-0212-7
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12272-010-0212-7