許多對掌性藥品 (chiral drugs) 在臨床上卻是使用其外消旋混合物 (racemic mixtures)，即兩鏡像異構物以50:50比例混合之消旋化物，而化學結構相似的兩鏡像異構物卻常有著不同的藥效與藥動性質。一般非對掌選擇性的藥物分析條件，得到的藥物血中濃度是個別鏡像異構物的總和，而非個別鏡像異構物的血中濃度，因此並無法對於對掌性藥品的立體選擇性動態學做定性或定量的探討。Mirtazapine是一種四環類抗憂鬱劑，具有兩個鏡像異構物，相關研究顯示mirtazapine鏡像異構物的藥物動力學存在有差異性，且造成差異的原因可能是因為mirtazapine鏡像異構物在生物轉化途徑或與藥物運輸子的作用不同有關。
因此本研究目的為首要開發並確效可定量生物體液中mirtazapine鏡像異構物濃度之對掌性毛細管電泳法。其次以大鼠小腸灌流實驗研究mirtazapine鏡像異構物在小腸吸收的機制。並以靜脈注射給予mirtazapine於大白鼠評估其立體選擇性動力學並探討是否具有劑量依性關係。
實驗結果已成功開發並確效一對掌性毛細管電泳法用來定量mirtazapine在動物體液內之濃度，且實際應用至大白鼠小腸灌流實驗及大白鼠體內動力學研究，且此分析方法經調整後也能合適地運用在定量人體血漿內之濃度。由小腸灌流實驗顯示，在灌流藥品濃度由5 μg/mL提高到250 μg/mL，其穩定狀態藥品吸收分率(Fabs)下降，推測mirtazapine鏡像異構物在小腸的吸收機轉應涉及腸道載體(intestinal carriers)的運輸，另外不論在灌流哪個藥品濃度下，兩鏡像異構物之Fabs皆無顯著差異，說明了mirtazapine鏡像異構物於小腸的吸收不具有立體選擇性。在大白鼠體內的劑量依性試驗顯示在靜脈注射1-10 mg/kg下，mirtazapine鏡像異構物在血漿中的藥動學呈現線性且具有立體選擇性，而mirtazapine及其代謝物在膽汁濃度高於血漿顯示其膽汁排除具有主動分泌的機制並可能涉及運輸載體調控。
整體而言，mirtazapine鏡像異構物在大白鼠小腸的吸收不具立體選擇性。在大白鼠體內的藥物動力學方面，mirtazapine鏡像異構物在大白鼠體內的動力學呈現線性，並且mirtazapine及其代謝物的膽汁排泄為一主動運輸並可能涉及運輸載體之調控。Mirtazapine鏡像異構物於體內之藥品動態具有差異性，將來仍須對於mirtazapine鏡像異構物的藥動機制做進一步的探討。

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.

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