西格列他钠的体外代谢

目的研究拟治疗2型糖尿病的创新化合物西格列他钠(chiglitazar)的体外代谢速率、代谢酶和代谢转化,为临床应用提供参考。方法采用高效液相-紫外检测(HPLC-UV)的方法测定肝微粒体孵育液中西格列他钠的浓度,用特异性抑制剂的方法分析化合物的代谢酶,用大鼠肝微粒体体外研究西格列他钠可能的代谢产物和代谢途径。结果建立了可靠的测定大鼠肝微粒体中西格列他钠的HPLC分析方法;体外半衰期方法求得西格列他钠的t1/2为27.2min,固有清除率(Clint)为50.9mL.min-1.g-1蛋白;代谢酶研究表明,西格列他钠主要被P450酶中的CYP3A亚型代谢;西格列他钠在大鼠肝微粒体中的代谢主要为羟基化和O-脱烷基化,采用LC/MSn分析共发现了8个代谢物。结论西格列他钠是代谢活跃的化合物,有必要研究代谢产物的活性及临床注意药物相互作用。

In vitro metabolism of chiglitazar

AIM To study the in vitro clearance rate, cytochrome P450 reaction phenotyping and metabolites of chiglitazar, a novel compound for treating diabetes. METHODSHPLC-UV assay was used to analyze chiglitazar concentration in microsomes incubation system. Phenotyping was determined with inhibitors of P450 enzymes. In vitrometabolites were proposed by incubating chiglitazar with rat microsomes and LC/MSⁿ method. RESULTSHPLC-UV assay method was validated and satisfied the quantification of chiglitazar. t _1/2 value of 27.2 min and scaled Cl _int value of 50.9 mL·min^-1·g^-1 protein were determined with 25 μmol·L^-1 chiglitazar by "in vitro t _1/2" method. The results of selective chemical inhibitors suggested that CYP3A be principal enzymes involved in the metabolism of chiglitazar in rat liver microsomes. Metabolic studies showed that chiglitazar was extensively metabolized by hydroxylation and O-dealkylation. A total of 8 metabolites were found in rat liver icrosomes incubation system. CONCLUSIONThe above data demonstrated that chiglitazar is transformed into metabolites easily by rat liver microsomes, so it is essential for studying the activities of metabolites and drug-drug reaction.