Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, Guangdong, China.
School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, Guangdong, China.
Curr Drug Metab. 2020;21(5):368-378. doi: 10.2174/1389200221666200512113731.
Drug-metabolizing enzymes and transporters play key roles in drug disposition and drug interactions. The alterations of their expression will influence drug pharmacokinetics and pharmacodynamics. However, the changes in the expression of enzymes and transporters in the disease state are still unclear.
Our study was to investigate the changes in the expression of main enzymes and drug transporters distributed in Adriamycin nephropathy rat liver, kidney, and intestine.
An intravenous injection with a single dose of Adriamycin (6mg/kg) was made to establish Adriamycin nephropathy (AN) model and normal groups were injected with normal saline. Serum was collected for lipid metabolism, renal, and hepatic function measurement. The real-time PCR and western blot were applied to determine the mRNA and protein expression of drug enzymes and transporters.
In the kidney, a greater expression of Mdr1, Mrp2, Mrp4 Oat2 and Oct2 mRNA was found in AN rats as compared with control rats. In the liver, the expression of Bcrp mRNA was more doubled or tripled than control groups and downregulation of Mdr1, Mrp2, Mrp4 and Bsep gene expression was found in AN rats. Besides, we observed a downward trend of Cyp1a2, Cyp3a4 and Cyp2c9 mRNA levels in AN groups. In the duodenum, the expression of Mdr1 and Mrp3 mRNA level was decreased, while Bcrp and Mrp2 mRNA were increased.
The changes in drug-metabolizing enzymes and transporters expression in AN rats were clarified, which may be beneficial for understanding the altered pharmacokinetics and pharmacodynamics of clinical drugs and reduce unexpected clinical findings for nephropathy patients.
药物代谢酶和转运体在药物处置和药物相互作用中发挥着关键作用。它们的表达改变将影响药物的药代动力学和药效动力学。然而，在疾病状态下，酶和转运体表达的变化仍不清楚。
本研究旨在探讨阿霉素肾病大鼠肝、肾和肠中主要分布的酶和药物转运体的表达变化。
采用单次静脉注射阿霉素（6mg/kg）建立阿霉素肾病（AN）模型，对照组注射生理盐水。采集血清进行脂质代谢、肾功能和肝功能检测。实时 PCR 和 Western blot 用于测定药物酶和转运体的 mRNA 和蛋白表达。
在肾脏中，与对照组相比，AN 大鼠的 Mdr1、Mrp2、Mrp4、Oat2 和 Oct2 mRNA 表达增加。在肝脏中，Bcrp mRNA 的表达是对照组的两倍或三倍以上，而 Mdr1、Mrp2、Mrp4 和 Bsep 基因的表达下调。此外，我们观察到 AN 组 Cyp1a2、Cyp3a4 和 Cyp2c9 mRNA 水平呈下降趋势。在空肠中，Mdr1 和 Mrp3 mRNA 水平降低，而 Bcrp 和 Mrp2 mRNA 水平升高。
阐明了 AN 大鼠药物代谢酶和转运体表达的变化，这可能有助于理解临床药物药代动力学和药效动力学的改变，减少肾病患者的意外临床发现。
