Reist M, Roy-de Vos M, Montseny J P, Mayer J M, Carrupt P A, Berger Y, Testa B
Université de Lausanne, Institut de Chimie Thérapeutique, Ecole de Pharmacie, Lausanne, Switzerland.
Drug Metab Dispos. 2000 Dec;28(12):1405-10.
Clopidogrel hydrogen sulfate, a thienopyridine derivative, is an ADP receptor antagonist that inhibits platelet aggregation. Clopidogrel is an enantiopure carboxylic ester of S-configuration. The R-enantiomer is devoid of antithrombotic activity and can provoke convulsions at high doses in animals. During preclinical safety evaluation, the possible chiral inversion of clopidogrel has, therefore, been investigated in vivo after repeated oral administration of different dose levels of clopidogrel to male and female rats. Due to rapid metabolism in the liver and low plasma levels of unchanged drug, possible chiral inversion was assessed by monitoring the plasma concentrations of the carboxylic acid metabolites, i.e., the (S)- and (R)-acid, by means of a stereoselective assay. The production of 4 to 8% of (R)-acid was observed. This could be the result of chiral inversion of either clopidogrel or its main metabolite, the (S)-acid. Thus, the possibility of nonenzymatic and enzymatic inversion of clopidogrel and its carboxylic acid metabolite was studied in vitro by chiral HPLC and (1)H NMR. Nonenzymatic chiral inversion of clopidogrel at 37 degrees C in 0.1 M phosphate buffers could be observed but was found to be slow, with estimated half-lives of 7 to 12 days, depending on the pH. The (S)-acid was configurationally fully stable up to 45 days in phosphate buffers. Neither clopidogrel nor its carboxylic acid metabolites were subject to enzymatic chiral inversion in isolated rat hepatocyte suspensions. We conclude that the nonenzymatic inversion of clopidogrel accounts for the 4 to 8% of chiral inversion seen in vivo in the rat.
硫酸氢氯吡格雷是一种噻吩并吡啶衍生物，是一种抑制血小板聚集的ADP受体拮抗剂。氯吡格雷是S构型的对映体纯羧酸酯。R-对映体没有抗血栓活性，在动物体内高剂量时可引发惊厥。因此，在临床前安全性评估期间，对雄性和雌性大鼠重复口服不同剂量水平的氯吡格雷后，在体内研究了氯吡格雷可能的手性转化。由于在肝脏中快速代谢且未改变药物的血浆水平较低，通过立体选择性测定法监测羧酸代谢物即（S）-酸和（R）-酸的血浆浓度来评估可能的手性转化。观察到产生了4%至8%的（R）-酸。这可能是氯吡格雷或其主要代谢物（S）-酸手性转化的结果。因此，通过手性高效液相色谱法和核磁共振氢谱（1H NMR）在体外研究了氯吡格雷及其羧酸代谢物的非酶促和酶促转化可能性。在37℃的0.1M磷酸盐缓冲液中可观察到氯吡格雷的非酶促手性转化，但发现其速度较慢，根据pH值估计半衰期为7至12天。（S）-酸在磷酸盐缓冲液中长达45天构型完全稳定。在分离的大鼠肝细胞悬液中，氯吡格雷及其羧酸代谢物均未发生酶促手性转化。我们得出结论，氯吡格雷的非酶促转化占大鼠体内所见手性转化的4%至8%。
