簡介：Sulpiride具有抗精神病及抗嘔吐的作用，屬於可逆的D2 receptor選擇性拮抗劑，較其他典型抗精神病藥物少有錐體外症候群副作用的發生，因此為臨床上常用的抗精神病藥物。市面上常見的sulpiride為其外消旋混合物，但實際上其分為R-sulpiride及S-sulpiride，兩鏡像異構物在人體內不論藥效或者藥動方面皆具有差異，在藥效方面，S-sulpiride為R-sulpiride的40倍，因此在歐洲及印度有levosulpiride的上市，但美國、加拿大及大部分的國家仍是使用其外消旋混合物，因此更彰顯sulpiride分旋研究的重要性。Sulpiride在人體中不被代謝，因此藥物輸送子對其分旋的藥動性質與療效影響更顯重要，目前已知同時投予sulpiride及PEPT1、OCTN1、OCTN2、p-gp數個藥物輸送子的受質後，sulpiride的血中濃度會有明顯的變化。本研究希望藉由開發sulpiride分旋分析方法來研究其於大鼠體內的藥物動態學，並探討同時投予藥物輸送子抑制劑(quinidine)時其藥動特性是否有所不同。

目的：本研究目的為首要開發並確效可定量生物體液中sulpiride鏡像異構物濃度之對掌性毛細管電泳法。其次為以靜脈注射及長時間靜脈輸注給予大白鼠sulpiride後，評估其立體選擇性動力學並探討其於藥物輸送子受到抑制前後的動態。

方法：以靜脈注射以及長時間靜脈輸注方式給予大白鼠消旋sulpiride，以及同時投予quinidine (藥物輸送子P-gp、OCTN1及OCTN2 的抑制劑)，觀測sulpiride 在大白鼠血中動態與膽汁排除之機制以及各器官組織中sulpiride的分布及鏡像選擇性。

結果：靜脈注射sulpiride 之活體實驗結果顯示，sulpiride於控制組血漿中動態並無立體選擇性，與動物實驗文獻相符，但在同時投予quinidine的抑制組中，S-sulpiride血中濃度遠大於R-sulpiride，膽汁亦然。但比較控制組與抑制組膽汁的R/S比值後，可發現抑制組膽汁中supiride的對掌選擇性降低，顯示quinidine會抑制sulpiride在膽汁的選擇性排除。而長時間靜脈輸注sulpiride 之活體實驗結果顯示，控制組在投予sulpiride至穩定狀態後，其血中濃度出現明顯的立體選擇性，各器官亦有些許立體選擇性，但在抑制組中則可見到血漿及器官中含藥量大幅上升，R/S 比值則漸趨近於一，顯示quinidine會降低sulpiride的排除及分布的立體選擇性。

結論：投予在大白鼠單一劑量靜脈注射sulpiride後，血中濃度不具立體選擇性，但膽汁中濃度則明顯為S-sulpiride大於R-sulpiride；靜脈輸注實驗則顯示血漿及各器官大部分為S-sulpiride大於R-sulpiride，抑制組的結果可看到R/S比值漸趨於一，由交互作用實驗可推測此選擇性是由於藥物輸送子P-gp、OCTN1及OCTN2 對於S-sulpiride 較具親和力所造成。目前的結果顯示在使用sulpiride時若同時投予quinidine，可能造成sulpiride或quinidine血中濃度過高，導致副作用甚至死亡率增加，因此在同時投予sulpiride及quinidine時，須特別注意sulpiride血中濃度以及藥物造成的副作用。

Introduction: Sulpiride is widely used in the treatment of schizophrenia, gastric and duodenal ulcers. It is a selectivantagonist at dopamine D2 receptor and has fewer extrapyramidal side effects than many of the older antipsychotic medications. Sulpiride is sold as a racemic mixture in many countries, but actually it is a chiral drug and its enantiomers have different pharmacokinetic and pharmacodynamic properties. It was recognized that S-sulpiride is 40 times more active than R-sulpiride in D2-receptor inhibition, so that S-sulpiride (levosulpiride) has shown greater efficacy than the racemic form in the treatment of depressive and somatoform disorders. And levosulpiride has been marketed recently in Europe and India. Because sulpiride is not metabolized in human, and it has been reported that the plasma sulpiride concentration after oral administration changes significantly by the concomitant administration of the substrates of PEPT1, OCTN1, OCTN2, P-glycoprotein. Therefore, it is important to study the role of drug transporters on the kinetics and dynamics of sulpiride enantiomers.
Purpose: The aim of this study was to develop and validate a sensitive and stereoselective capillary electrophoretic (CE) method for the analysis of sulpiride in biological fluids, and to examine the kinetics of sulpiride enantiomers in rats using this enantioselective capillary electrophoresis method.
Methods: Enantioselective pharmacokinetic, biliary excretion and organ cumulation of sulpiride in SD rats was studied following intravenous bolus and intravenous infusion of racemic sulpiride alone or in combination with quinidine, a well-known Pgp, OCTN1 and OCTN2 inhibitor.
Results:
A simple and sensitive enantioselective CE method for the quantification of sulpiride enantiomers was developed and applied successfully to examine the stereoselective pharmacokinetics of sulpiride in rats. The disposition kinetics of sulpiride in plasma was not stereoselective. In contrast, biliary concentration of S-sulpiride was significant great than that of R-sulpiride. After coadministrated with quinidine, significant stereoselectivity was observed for sulpiride enantiomers both in plasma and bile. And the biliary chiral selectivity was decreased in the presence of quinidine. These results indicated that sulpiride is transported across bile duct by a carrier-mediated process. Following continuous intravenous infusion of sulpiride to rats alone, there were significant differences between the concentrations of R- and S-sulpiride in plasma and some organs. However these differences were diminished in the presence of quinidine. These results indicated that quinidine may inhibit the stereoselective elimination of sulpiride.
Conclusion: Sulpiride displayed enantioselective pharmacokinetics in rats, which was probably due to difference in the affinity of drug transporters for sulpiride enantiomers. The dramatic increase in sulpiride plasma concentration after coadministration with quinidine suggests the possibility of drug–drug interaction between sulpiride and quinidine. The findings of the present study provide important information for enantioselective kinetics and drug interaction of sulpiride.

Agranat II and Caner H (1999) Intellectual property and chirality of drugs. Drug Discov Today 4:313-321.
Blaschke G and Chankvetadze B (2000) Enantiomer separation of drugs by capillary electromigration techniques. J Chromatogr A 875:3-25.
Bres J and Bressolle F (1991) Pharmacokinetics of sulpiride in humans after intravenous and intramuscular administrations. J Pharm Sci 80:1119-1124.
Brewster ME and Loftsson T (2007) Cyclodextrins as pharmaceutical solubilizers. Adv Drug Deliv Rev 59:645-666.
Caldwell J (2001) Do single enantiomers have something special to offer? Hum Psychopharmacol 16:S67-S71.
Emi Y, Tsunashima D, Ogawara K, Higaki K and Kimura T (1998) Role of P-glycoprotein as a secretory mechanism in quinidine absorption from rat small intestine. J Pharm Sci 87:295-299.
Gubitz G and Schmid MG (2001) Chiral separation by chromatographic and electromigration techniques. A review. Biopharm Drug Dispos 22:291-336.
Ha PT, Hoogmartens J and Van Schepdael A (2006) Recent advances in pharmaceutical applications of chiral capillary electrophoresis. J Pharm Biomed Anal 41:1-11.
Hutt AJ (2007) Chirality and pharmacokinetics: an area of neglected dimensionality? Drug Metabol Drug Interact 22:79-112.
Imondi AR, Alam AS, Brennan JJ and Hagerman LM (1978) Metabolism of sulpiride in man and rhesus monkeys. Arch Int Pharmacodyn Ther 232:79-91.
Jain R, Majumdar S, Nashed Y, Pal D and Mitra AK (2004) Circumventing P-glycoprotein-mediated cellular efflux of quinidine by prodrug derivatization. Mol Pharm 1:290-299.
Jenner P, Clow A, Reavill C, Theodorou A and Marsden CD (1980) Stereoselective actions of substituted benzamide drugs on cerebral dopamine mechanisms. J Pharm Pharmacol 32:39-44.
Juvancz Z, Kendrovics RB, Ivanyi R and Szente L (2008) The role of cyclodextrins in chiral capillary electrophoresis. Electrophoresis 29:1701-1712.
Kamizono A, Inotsume N, Fukushima S, Nakano M and Okamoto Y (1993) Disposition of enantiomers of sulpiride in humans and rats. Biopharm Drug Dispos 14:475-481.
Lacombe O, Woodley J, Solleux C, Delbos JM, Boursier-Neyret C and Houin G (2004) Localisation of drug permeability along the rat small intestine, using markers of the paracellular, transcellular and some transporter routes. Eur J Pharm Sci 23:385-391.
Lamhonwah AM, Ackerley C, Onizuka R, Tilups A, Lamhonwah D, Chung C, Tao KS, Tellier R and Tein I (2005) Epitope shared by functional variant of organic cation/carnitine transporter, OCTN1, Campylobacter jejuni and Mycobacterium paratuberculosis may underlie susceptibility to Crohn's disease at 5q31. Biochem Biophys Res Commun 337:1165-1175.
Lamhonwah AM, Wong J, Tam C, Mai L and Tein I (2009) Organic cation/carnitine transporter family expression patterns in adult murine heart. Pathol Res Pract 205:395-402.
Lu H (2007) Stereoselectivity in drug metabolism. Expert Opin Drug Metab Toxicol 3:149-158.
Mangelings D and Vander Heyden Y (2008) Chiral separations in sub- and supercritical fluid chromatography. J Sep Sci 31:1252-1273.
Mizuchi A, Kitagawa N, Saruta S and Miyachi Y (1982) Characteristics of [3H]sultopride binding to rat brain. Eur J Pharmacol 84:51-59.
Moghaddam B and Bunney BS (1990) Acute effects of typical and atypical antipsychotic drugs on the release of dopamine from prefrontal cortex, nucleus accumbens, and striatum of the rat: an in vivo microdialysis study. J Neurochem 54:1755-1760.
Muller MJ, Hartter S, Kohler D and Hiemke C (2001) Serum levels of sulpiride enantiomers after oral treatment with racemic sulpiride in psychiatric patients: a pilot study. Pharmacopsychiatry 34:27-32.
Niwa T, Inoue S, Shiraga T and Takagi A (2005) No inhibition of cytochrome P450 activities in human liver microsomes by sulpiride, an antipsychotic drug. Biol Pharm Bull 28:188-191.
Ohashi R, Tamai I, Yabuuchi H, Nezu JI, Oku A, Sai Y, Shimane M and Tsuji A (1999) Na(+)-dependent carnitine transport by organic cation transporter (OCTN2): its pharmacological and toxicological relevance. J Pharmacol Exp Ther 291:778-784.
Ranade VV and Somberg JC (2005) Chiral cardiovascular drugs: an overview. Am J Ther 12:439-459.
Roden DM (1996) Is there a need for new antiarrhythmic drugs? Arch Mal Coeur Vaiss 89 Spec No 1:13-18.
Scriba GK (2008) Cyclodextrins in capillary electrophoresis enantioseparations--recent developments and applications. J Sep Sci 31:1991-2011.
Takahashi H and Echizen H (2001) Pharmacogenetics of warfarin elimination and its clinical implications. Clin Pharmacokinet 40:587-603.
Tsuji A and Tamai I (1996) Carrier-mediated intestinal transport of drugs. Pharm Res 13:963-977.
Watanabe K, Sawano T, Endo T, Sakata M and Sato J (2002a) Studies on intestinal absorption of sulpiride (2): transepithelial transport of sulpiride across the human intestinal cell line Caco-2. Biol Pharm Bull 25:1345-1350.
Watanabe K, Sawano T, Jinriki T and Sato J (2004) Studies on intestinal absorption of sulpiride (3): intestinal absorption of sulpiride in rats. Biol Pharm Bull 27:77-81.
Watanabe K, Sawano T, Terada K, Endo T, Sakata M and Sato J (2002b) Studies on intestinal absorption of sulpiride (1): carrier-mediated uptake of sulpiride in the human intestinal cell line Caco-2. Biol Pharm Bull 25:885-890.
Watzig H and Gunter S (2003) Capillary electrophoresis-a high performance analytical separation technique. Clin Chem Lab Med 41:724-738.
Xu X and Stewart JT (2000) Chiral analysis of selected dopamine receptor antagonists in serum using capillary electrophoresis with cyclodextrin additives. J Pharm Biomed Anal 23:735-743.
Yabuuchi H, Tamai I, Nezu J, Sakamoto K, Oku A, Shimane M, Sai Y and Tsuji A (1999) Novel membrane transporter OCTN1 mediates multispecific, bidirectional, and pH-dependent transport of organic cations. J Pharmacol Exp Ther 289:768-773.
孫青(龍天), 劉長海, 李國棟, 俞世沖, 柴逸峰, 吳秋業 (2004) β-環糊精硫酸酯的合成及其在舒必利毛細管電泳拆分中的應用. 第二軍醫大學學報 25:1259-1260.
祝仕清, 牛長群, ZHU Shi-qing, NIU Chang-qun (2006) 左舒必利的毛細管電泳手性分離與純度檢查. 中國新藥雜志 15:995-996.