Biopharmaceutics, NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China.
Integrated Traditional Chinese and Western Medicine Hospital of Southern Medical University, Southern Medical University, Guangzhou 510515, China.
Molecules. 2022 Jan 21;27(3):704. doi: 10.3390/molecules27030704.
With the widespread clinical use of drug combinations, the incidence of drug-drug interactions (DDI) has significantly increased, accompanied by a variety of adverse reactions. Drug transporters play an important role in the development of DDI by affecting the elimination process of drugs in vivo, especially in the pathological state. Tubulointerstitial fibrosis (TIF) is an inevitable pathway in the progression of chronic kidney disease (CKD) to end-stage renal disease. Here, the dynamic expression changes of eleven drug transporters in TIF kidney have been systematically investigated. Among them, the mRNA expressions of Oat1, Oat2, Oct1, Oct2, Oatp4C1 and Mate1 were down-regulated, while Oat3, Mrp2, Mrp4, Mdr1-α, Bcrp were up-regulated. Pearson correlation analysis was used to analyze the correlation between transporters and Creatinine (Cr), OCT2 and MATE1 showed a strong negative correlation with Cr. In contrast, Mdr1-α exhibited a strong positive correlation with Cr. In addition, the pharmacokinetics of cimetidine, ganciclovir, and digoxin, which were the classical substrates for OCT2, MATE1 and P-glycoprotein (P-gp), respectively, have been studied. These results reveal that changes in serum creatinine can indicate changes in drug transporters in the kidney, and thus affect the pharmacokinetics of its substrates, providing useful information for clinical use.
随着药物联合应用的广泛临床应用，药物相互作用（DDI）的发生率显著增加，同时伴有多种不良反应。药物转运体通过影响体内药物的消除过程，特别是在病理状态下，在药物相互作用的发生中起着重要作用。肾小管间质纤维化（TIF）是慢性肾脏病（CKD）向终末期肾病进展的必然途径。在这里，我们系统地研究了 TIF 肾脏中十一种药物转运体的动态表达变化。其中，Oat1、Oat2、Oct1、Oct2、Oatp4C1 和 Mate1 的 mRNA 表达下调，而 Oat3、Mrp2、Mrp4、Mdr1-α、Bcrp 则上调。通过 Pearson 相关性分析，分析了转运体与肌酐（Cr）之间的相关性，OCT2 和 MATE1 与 Cr 呈强负相关。相反，Mdr1-α与 Cr 呈强正相关。此外，还研究了西咪替丁、更昔洛韦和地高辛的药代动力学，它们分别是 OCT2、MATE1 和 P 糖蛋白（P-gp）的经典底物。这些结果表明，血清肌酐的变化可以提示肾脏中药物转运体的变化，从而影响其底物的药代动力学，为临床应用提供有用的信息。
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