摘要
目的:用大鼠肝微粒体研究盐酸雷诺嗪代谢的性别差异及选择性CYP抑制剂对其代谢的影响。方法:盐酸雷诺嗪分别与雌性或雄性大鼠的肝微粒体温孵,抑制试验是在微粒体中先加入选择性抑制剂温孵30 min后,再加入盐酸雷诺嗪温孵。温孵后的样品中加入内标咖啡因,碱化后乙醚提取,取上清液水浴挥干,流动相溶解后采用梯度洗脱进行HPLC测定。结果:盐酸雷诺嗪在大鼠肝微粒体内被迅速代谢为6个Ⅰ相代谢产物,雄性大鼠微粒体酶的代谢能力强于雌性大鼠。CYP3A特异性抑制剂酮康唑(Ket)、CYP1A2特异性抑制剂α-萘磺酮(-αNaph)和CYP2D2特异性抑制剂奎尼丁(Qui)可以明显地抑制肝微粒体中盐酸雷诺嗪的代谢,其中Ket的抑制能力最强;而二乙二硫氨基甲酸酯(DDC)和磺胺苯吡唑(Sul)对盐酸雷诺嗪的代谢无明显影响。结论:研究提示盐酸雷诺嗪在雌雄大鼠肝微粒体内的代谢有极其显著性差异,其主要原因是CYP3A酶在大鼠肝微粒体中具有性别差异性。
Aim： To study the gender difference in ranolazine metabolism and the effects of selective cytochrome P-450 （CYP450） inhibitors on the metabolism of ranolazine in rat liver microsomes. Methods： Ranolazine was incubated with male and female rat liver microsomes, respectively. 30 min incubation with selective CYP450 inhibitors was followed by the addition of ranolazine into the matrix. Caffeine was used as the internal standard. After alkalization, the aliquots were extracted by diethyl ether and determined by HPLC operated in the mode of gradient elution. Results： Ranolazine was rapidly metabolized to six phase Ⅰ metabolites in rat liver microsomes. The metabolism of ranolazine in male rat liver microsomes was more extensive than that in female ones. Ketoconazole （Ket）,quinidine （Qui）, and α- Naphthoflavone （α-Naph） had inhibitory effects on the metabolism of ranolazine. In particularly Ket shown the most significant action. It was further found that Sulfaphenazole （Sul） and diethyldithiocarbamate （DDC） had little or no inhibitory effects on ranolazine metabolism. Conclusion： The observed gender differences in ranolazine metabolism might be due to the different characteristics of CYP3A inherited in male and female rat liver microsomes.
出处
《中国药科大学学报》
CAS
CSCD
北大核心
2006年第5期450-455,共6页
Journal of China Pharmaceutical University
基金
国家高技术研究发展计划("八六三"计划)资助项目(No.2003AA2Z347A)
江苏省药物代谢动力学重点实验室资助项目(No.BM2001201)~~
