Abstract
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.
Highlights
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, Laboratory Animal Management Center, Southern Medical University, Guangzhou 510515, China; Abstract: 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
This experiment explored the relationship between major kidney transporters and creatinine, creatinine clearance, and renal fibrosis area
The development of modeling time in the Tubulointerstitial fibrosis (TIF) pathological model of rats was studied to infer the relationship between creatinine, creatinine clearance and kidney transporters
Summary
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, Laboratory Animal Management Center, Southern Medical University, Guangzhou 510515, China; Abstract: 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. 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 affect the pharmacokinetics of its substrates, providing useful information for clinical use. The Food and Drug Administration and National Medical Products Administration of China have pointed out that eleven drug transporters in the kidneys, including organic anion transporter 1 (OAT1), organic anion transporter 1 (OAT3), organic anion transporter polypeptide 4C1 (OATP4C1), organic cation transporter (OCT2), P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), multi-drug and toxin extrusion protein 1 (MATE1), published maps and institutional affiliations. Tubulointerstitial fibrosis (TIF) is a common pathological change in CKD progression to end-stage renal disease [7,8]
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