Stereoselective Pharmacokinetics of Mirtazapine in Rats

• Main Authors: Yu-Hsin Chang, 張祐鑫
• Other Authors: Chen-Hsi Chou
• Format: Others
• Language: zh-TW
• Published: 2008
• Online Access: http://ndltd.ncl.edu.tw/handle/52604455872421499834

碩士 === 國立成功大學 === 臨床藥學研究所 === 96 === Introduction: Many chiral drugs are used as their racemic mixtures in clinical practice, although it is well recognised that the enantiomers of a chiral drug may possess different pharmacokinetic and pharmacodynamic properties. Many studies dealing with chiral drugs which are administered as their racemates rely on non-stereoselective analytical techniques. It was shown that the use of such an analytical method can lead to the collection of data which may be both quantitatively and qualitatively inaccurate with respect to the individual enantiomers. Mirtazapine is a tetracyclic antidepressant that has two enantiomers. Several studies show that mirtazapine’s enantiomers display differences in disposition kinetics, probably owing to differences in both biotransformation and drug transport between the mirtazapine enantiomers Purpose: The aim of this study was to develop and validate a sensitive and enantioselective capillary electrophoretic (CE) method for the analysis of mirtazapine in biological fluids, and to apply the method to characterize the stereopharmacokinetics of mirtazapine in rats following intravenous administration. Besides, a rat small intestinal perfusion model was used to evaluate the absorption of mirtazapine enantiomers. Results: A simple and sensitive enantioselective capillary electrophoretic (CE) method for the quantification of mirtazapine enantiomers in biological fluids was developed and applied successfully to examine the stereoselective pharmacokinetics of mirtazapine in rats. The enantioselective capillary electrophoretic (CE) method was also apppied to determine the concentration of mirtazapine enantiomers in intestinal perfusate samples and human plasma successfully. In rat intestinal perfusion studies, with increasing perfusate mirtazapine concentration, the fraction of dose absorbed (Fabs) at steady state is decreasing. The concentration-dependent uptake of mirtazapine indicated that mirtazapine was absorbed in rat intestine by passive and carrier-mediated mechanisms. The absorption kinetics of mirtazapine enantiomers from intestine were similar, and did not exhibit stereoselectivity. Following bolus injection of 1-10 mg/kg to rats, the disposition of mirtazapine enantiomers in plasma was linear and stereoselective. The concentration of mirtazapine and its metabolites in bile was greater than that in the plasma, suggesting that biliary transport of mirtazapine and its metabolite may be mediated by drug transporters. Conclusion: In summary, no stereoselectivity was displayed in the absorption of the mirtazapine enantiomers in rats. The disposition of mirtazapine enantiomers in plasma was linear, and distribution and elimination of mirtazapine enantiomers show stereoselective differences. The active biliary secretion of mirtazapne was found, suggesting that biliary transport of mirtazapine may be mediated by drug transporters. As mirtazapine displayed stereopharmacokinetics, further studies will be needed to fully eclucidate the detail mechanisms of its stereopharmacokinetics.