簡介: Amisulpride為非典型的抗精神病藥物，其在低劑量時對於突觸前dopamine受器 (D2, D3)具有較高親和性，增加dopamine傳導，而對精神病的負性症狀具有改善效果。高劑量則是對突觸後的dopamine受器 (D2, D3)具有拮抗效果，而能改善正性症狀。特別的是R(+) amisulpride能夠降低由S(-) amisulpride或是haloperidol所引起之catalepsy，也稍微解釋了雖然amisulpride作用的受器為類似典型抗精神病藥物的dopamine受器，然而卻像非典型抗精神病藥物般有較少的副作用。Amisulpride於靜脈注射給予後，約50至70%自腎臟及15%自膽汁以原型態排除，僅僅只有10至15%經由肝臟代謝成兩個不具活性的代謝物。由於amisulpride的肝代謝率很低且代謝物無活性，因此肝臟酵素的誘導及抑制對於amisulpride的影響較小。相對的藥物輸送子對於amisulpride藥動性質與療效的影響更顯重要，然而目前此方面的文獻仍較為缺乏。

目的：本研究目的在利用具鏡像選擇性的毛細管電泳分析方法，探討amisulpride於鼠體及人體內的動態。

方法: 以口服及靜脈注射方式給予大白鼠消旋amisulpride或是同時投予藥物輸送子P-gp抑制劑cyclosporine，觀測amisulpride在大白鼠血中動態與膽汁排除之機制以及其鏡像選擇性。而人體動態分布方面，則是藉由分析人體口服amisulpride生體相等性試驗之血漿檢品，以研究amisulpride個別鏡像異構物於國人之動力學及其鏡像選擇性，並探討amisulpride個別鏡像異構物之生體相等性。

結果：Amisulpride之活體實驗結果顯示，控制組及交互作用組中S-amisulpride於膽汁中之排除量皆為R-amisulpride的2倍；膽汁中amisulpride濃度曲線下面積遠大於血漿中濃度曲線下面積，且此比值在加入藥物輸送子抑制劑大幅下降至接近一；當同時口服投予amisulpride及cyclosporine，會顯著增加口服amisulpride的血中濃度曲線下面積；證實amisulpride於大白鼠之血中動態及膽汁排除具有藥物輸送子調控的主動分泌且鏡像選擇性的機制；而藉由分析生體相等性試驗之台灣人血漿檢品，已成功地描述amisulpride個別鏡像異構物於國人之鏡像選擇性動力學。

結論：Amisulpride於大白鼠及人體的藥物動力學皆具鏡像選擇性。在大白鼠體內，不論血中或是膽汁中濃度，在給藥後任何時間點皆為S-amisulpride大於R-amisulpride；於大白鼠活體交互作用實驗的結果顯示，此選擇性可能是由於藥物輸送子Pgp對於S-amisulpride較具親和力所造成。

Introduction: Amisulpride is an atypical antipsychotic belonging to the class of substituted benzamides. It has preferential affinity for presynaptic D2 and D3 receptors at low doses (<10 mg/kg), leading to enhanced dopamine transmission and may be beneficial for negative syndrome, whereas at higher doses it antagonise postsynaptic D2 and D3 receptors, thus reducing dopamine transmission and improve positive syndrome. Interestingly, R(+)-amisulpride can reduce the catalepsy induced by S(-)-amisulpride or haloperidol, this may explain why amisulpride is not work as atypical antipsychotic but act like it. Amisulpride undergoes minimal hepatic metabolism and produces two inactive metabolites via N-dealkylation and oxidation. Around 50-70% and 15% of dose was recovered unchanged in urine and feces, respectively, after intravenous administration. The induction or inhibition of hepatic enzyme is less important due to its weak metabolism. On the contrary, the role of drug transporters on the kinetics and dynamics of amisulpride enantiomers is of great importance.

Purpose: The aim of this study was to examine the kinetics of amisulpride enantiomers in rats and humans using a modified enantioselective capillary electrophoresis method.

Methods: Enantioselective pharmacokinetic and biliary excretion of amisulpride in SD rats was explored following intravenous and oral administration of racemic amisulpride alone or in combination with a well-known Pgp inhibitor, cyclosporine. The enantioselective kinetics of amisulpride in humans was examined in a bioequivalence study conducted in Taiwanese subjects.

Results: The amount of S-amisulpride excreted in bile was twice higher than that of R-amisulpride both in control or inhibition group. The area under concentration-time curves (AUCs) of amisulpride enantiomers in bile were much higher than those in plasma, and this difference was almost diminished in the presence of cyclosporine. The AUC of both amisulpride enantiomers in plasma was significantly increased when cyclosporine was co-administered orally. These results confirmed the absorption and disposition kinetics and active biliary excretion of amisulpride was enantioselective. In human study, the enantioselective pharmacokinetics of amisulpride in Taiwanese was successfully elucidated.

Conclusion: The pharmacokinetics of amisulpride is enantioselective both in rats and humans. After administration to the rat, the concentration of in plasma and bile S-amisulpride is always higher than those of R-amisulpride. Results of animal study indicated this enantioselective pharmacokinetics is probably due to the difference in affinity of Pgp to the enantiomers.

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