PMID- 35754503 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20220716 IS - 1663-9812 (Print) IS - 1663-9812 (Electronic) IS - 1663-9812 (Linking) VI - 13 DP - 2022 TI - JBP485, A Dual Inhibitor of Organic Anion Transporters (OATs) and Renal Dehydropeptidase-I (DHP-I), Protects Against Imipenem-Induced Nephrotoxicity. PG - 938813 LID - 10.3389/fphar.2022.938813 [doi] LID - 938813 AB - Imipenem (IMP) possesses a broad spectrum of antibacterial activity; however, nephrotoxicity limits its clinical application in patients with renal insufficiency. In our previous studies, a dipeptide, JBP485, a dipeptide with the chemical structure cyclo-trans-4-L-hydroxyprolyl-L-serine, was found to attenuate drug-induced kidney injury. The current study aimed to explore whether JBP485 could relieve IMP-induced kidney injury and clarify the potential molecular pharmacokinetic mechanism. The effects of JBP485 on IMP nephrotoxicity were evaluated in rabbits and human kidney 2 (HK-2) cells. Drug-drug interactions (DDIs) mediated by organic anion transporters (OATs) and dehydropeptidase-I (DHP-I) were explored through pharmacokinetic studies in rats, metabolism assays in the kidney, and uptake studies in OAT-over-expressing cells. The results revealed that JBP485 significantly ameliorated IMP-induced nephrotoxicity in rabbits. Further, incubation of HK-2 cells with JBP485 or cilastatin markedly improved the cell survival rate, inhibited apoptosis and attenuated mitochondrial damage by improving the stability of IMP and reducing its intracellular accumulation. This suggests that DHP-I and OATs might be involved in the protective effect of JBP485. Furthermore, coadministration with JBP485 significantly increased the IMP's plasma concentration as well as the area under the plasma concentration-time curve (AUC), while decreasing IMP renal clearance and cumulative urinary excretion. Moreover, JBP485 reduced IMP uptake in kidney slices and OAT1/3-human embryonic kidney 293 (HEK293) cells. At the same time, the metabolism of IMP by DHP-I was inhibited by JBP485 with an IC(50) value of 12.15 +/- 1.22 muM. Finally, the molecular docking assay revealed a direct interaction between JBP485 and OAT1/3 or DHP-I. In conclusion, JBP485 protected against IMP nephrotoxicity in rabbits and HK-2 cells by improving IMP stability and reducing its intracellular accumulation via simultaneous inhibition of renal OATs and DHP-I. JBP485 is a promising renoprotective agent and could serve as an effective supplement to reduce IMP-induced adverse renal reactions in the clinical setting. CI - Copyright (c) 2022 Wang, Wang, Wu, Meng, Jin, Sun, Kaku, Chen, Huo and Liu. FAU - Wang, Chong AU - Wang C AD - Institute of Integrative Medicine, Dalian Medical University, Dalian, China. AD - Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian, China. AD - Provincial Key Laboratory for Pharmacokinetics and Transport, Liaoning Dalian Medical University, Dalian, China. FAU - Wang, Changyuan AU - Wang C AD - Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian, China. AD - Provincial Key Laboratory for Pharmacokinetics and Transport, Liaoning Dalian Medical University, Dalian, China. FAU - Wu, Jingjing AU - Wu J AD - Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian, China. AD - Provincial Key Laboratory for Pharmacokinetics and Transport, Liaoning Dalian Medical University, Dalian, China. FAU - Meng, Qiang AU - Meng Q AD - Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian, China. AD - Provincial Key Laboratory for Pharmacokinetics and Transport, Liaoning Dalian Medical University, Dalian, China. FAU - Jin, Huan AU - Jin H AD - Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian, China. AD - Provincial Key Laboratory for Pharmacokinetics and Transport, Liaoning Dalian Medical University, Dalian, China. FAU - Sun, Huijun AU - Sun H AD - Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian, China. AD - Provincial Key Laboratory for Pharmacokinetics and Transport, Liaoning Dalian Medical University, Dalian, China. FAU - Kaku, Taiichi AU - Kaku T AD - Japan Bioproducts Industry Co. Ltd, Tokyo, Japan. FAU - Chen, Jing AU - Chen J AD - School of Chemistry and Materials Science, University of Science and Technology of China, Hefei, China. FAU - Huo, Xiaokui AU - Huo X AD - Pharmaceutical Research Center, Second Affiliated Hospital, Dalian Medical University, Dalian, China. FAU - Liu, Kexin AU - Liu K AD - Institute of Integrative Medicine, Dalian Medical University, Dalian, China. AD - Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian, China. AD - Provincial Key Laboratory for Pharmacokinetics and Transport, Liaoning Dalian Medical University, Dalian, China. LA - eng PT - Journal Article DEP - 20220608 PL - Switzerland TA - Front Pharmacol JT - Frontiers in pharmacology JID - 101548923 PMC - PMC9214236 OTO - NOTNLM OT - DDI OT - DHP-I OT - Imipenem OT - JBP485 OT - OATs COIS- Author TK is employed by Japan Bioproducts Industry Co. Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. EDAT- 2022/06/28 06:00 MHDA- 2022/06/28 06:01 PMCR- 2022/06/08 CRDT- 2022/06/27 03:35 PHST- 2022/05/08 00:00 [received] PHST- 2022/05/23 00:00 [accepted] PHST- 2022/06/27 03:35 [entrez] PHST- 2022/06/28 06:00 [pubmed] PHST- 2022/06/28 06:01 [medline] PHST- 2022/06/08 00:00 [pmc-release] AID - 938813 [pii] AID - 10.3389/fphar.2022.938813 [doi] PST - epublish SO - Front Pharmacol. 2022 Jun 8;13:938813. doi: 10.3389/fphar.2022.938813. eCollection 2022.