目的 体外研究二-(4-氯苯甲酰异羟肟酸)二正丁基合锡(DBDCT)在大鼠肝微粒体中的代谢及酶促动力学,并探讨参与其代谢的主要CYP450同工酶亚型。方法 优化二-(4-氯苯甲酰异羟肟酸)二正丁基合锡在大鼠肝微粒体中的孵育条件,并对其在不同酶源中的酶促动力学进行研究;通过体外抑制实验初步探讨参与二-(4-氯苯甲酰异羟肟酸)二正丁基合锡代谢的主要CYP450同工酶的亚型。结果 不同酶源代谢实验显示,苯巴比妥(PB)、地塞米松(Dex)诱导组和空白对照组比较有显著性差异,而β-萘黄酮(BNF)组和空白对照组无明显差异;抑制实验显示酮康唑对二-(4-氯苯甲酰异羟肟酸)二正丁基合锡的代谢有较强的抑制作用;结论 二-(4-氯苯甲酰异羟肟酸)二正丁基合锡在大鼠肝微粒体中代谢较快,CYP3A在催化二-(4-氯苯甲酰异羟肟酸)二正丁基合锡代谢中起了主导作用,CYP2C9可能部分参与,而CYP1A对二-(4-氯苯甲酰异羟肟酸)二正丁基合锡的代谢无明显催化作用;提示二-(4-氯苯甲酰异羟肟酸)二正丁基合锡与经上述同工酶代谢的药物联合应用时,应注意药物之间相互作用的可能性。
Abstract
Objective To study the in vitro metabolism and enzyme kinetics of di-n-butyl-(4-chlorobenzohydroxamato) tin(IV) chloride in rat liver microsomes, and to identify the major cytochrome P450 isozymes involved in the metabolism of di-n-butyl-(4-chlorobenzohydroxamato) tin(IV) chloride in rat liver microsomes. Methods By optimizing the incubation conditions of di-n-butyl-(4-chlorobenzohydroxamato) tin(IV) chloride in rat liver microsomes, the enzyme kinetics in different enzyme sources was researched; the cytochrome P450 isozymes involved in metabolism of di-n-butyl-(4-chlorobenzohydroxamato) tin(IV) chloride were preliminarily explored through in vitro inhibition experiments. Results Different enzyme source metabolism experiments showed that between phenobarbital(PB) and desamethasone(Dex) induction groups and blank control group there had significant differences, but between the BNF group and blank control group there had no significant difference; the inhibition experiments revealed that ketoconazole had strong inhibition effect on di-n-butyl-(4-chlorobenzohydroxamato) tin(IV) chloride metabolism. Conclusion CYP3A plays a leading role in di-n-butyl-(4-chlorobenzohydroxamato) tin(IV) chloride metabolism, and CYP2C9 may be partly involved. CYP1A has no catalysis action on metabolism of di-n-butyl-(4-chlorobenzohydroxamato) tin(IV) chloride. The Results suggest that attention should be paid to the possibility of drug interactions when di-n-butyl-(4-chlorobenzohydroxamato) tin(IV) chloride is combined with the drugs metabolized by above-mentioned isozymes.
关键词
二-(4-氯苯甲酰异羟肟酸)二正丁基合锡 /
体外代谢 /
高效液相色谱法 /
肝微粒体 /
细胞色素P450
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Key words
di-n-butyl-(4-chlorobenzohydroxamato) tin(IV) chloride /
in vitro metabolism /
HPLC /
liver microsome /
CYP450
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中图分类号：
R965
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参考文献
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脚注
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基金
国家自然科学基金资助项目(30973603);国家“重大新药创制”科技重大专项(2009ZX09103-104)
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