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姜黄素对洛伐他汀在非酒精性脂肪肝大鼠体内药代动力学行为的影响

Influence of curcumin on the pharmacokinetics of lovastatin in rats with fatty liver disease

  • 摘要: 考察姜黄素对非酒精性脂肪肝的治疗作用及洛伐他汀在正常、非酒精性脂肪肝模型大鼠及姜黄素治疗大鼠体内的药代动力学行为变化。采用高脂饮食饲养大鼠造成非酒精性脂肪肝病理模型,通过血清生化分析和肝组织病理切片HE染色确证造模成功,在该模型下研究姜黄素的治疗对洛伐他汀药代动力学行为的影响;运用LC-MS法测定洛伐他汀在大鼠体内的血药浓度,计算药代动力学参数,比较其在正常大鼠、脂肪肝模型大鼠及姜黄素治疗大鼠体内的药代动力学行为差异;Western blot法测定大鼠肝脏CYP3A2的表达。长期给予高脂饲料喂养大鼠造成非酒精性脂肪肝模型使得洛伐他汀在血浆中的暴露显著升高,相应的AUC0-∞升高到正常对照组的1.53倍,半衰期延长到正常对照组的2.54倍,而姜黄素的治疗使AUC0-∞和半衰期都有明显降低,提示长期使用保肝药会改变药物在肝病状态下的药代动力学参数,其原因很可能是由于肝脏病理状态下CYP3A2的表达减少而姜黄素的治疗使其表达量增加所致。因此,在使用保肝药治疗脂肪肝及代谢综合征时要注意与联用药物之间可能存在的药物-药物相互作用,保证临床用药安全有效。

     

    Abstract: Non-alcoholic fatty liver disease is always accompanied by hyperlipemia, hypercholesterolemia and hypertension requiring to multiple drugs for the treatment at the same time, which is quite possible to incur drug/drug interactions. This study aimed at investigating the pharmacokinetics of lovastatin, which is used for lowering cholesterol in those with hypercholesterolemia and hyperlipemia, in fatty liver disease rats treated with or without curcumin, a hepatoprotective agent. Serum biochemical analysis and histopathological study were undertaken to verify that a proper non-alcoholic fatty liver rat model was established for our pharmacokinetic study and the plasma concentration of lovastatin was determined in normal rats, high fat diet fed rats treated with or without curcumin. High fat diet causing rats fatty liver disease resulted in a nearly 1. 53-fold enhancement of plasma exposure of lovastatin, as well as 2. 54-fold of t1/2 of model group than the normal group. Curcumin treatment reversed the plasma exposure almost to the control level, as well as the level of cmax and t1/2. The main reason might be that hepatic CYP3A2 expression decreased in high fat diet fed rats while curcumin treatment largely enhanced CYP3A2 expression. This study suggested that long-term treatment with hepatoprotective agent curcumin would influence the pharmacokinetic behaviour of other drugs and the drug/drug interaction between hepatoprotective agents and co-prescribed drugs should be of concern during liver injury.

     

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