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In Vitro Evaluation of Cimetidine Reno‐protective Effects on Cisplatin‐Induced Kidney Injury
Author(s) -
Mody Hardik,
Vaidya Tanaya,
Lesko Lawrence,
AitOudhia Sihem
Publication year - 2019
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2019.33.1_supplement.671.4
Subject(s) - cimetidine , cisplatin , kidney , pharmacology , apoptosis , toxicity , in vitro , chemistry , in vivo , stimulation , medicine , biology , biochemistry , chemotherapy , microbiology and biotechnology
Objectives Cisplatin (CIS), a platinum‐based drug, is one of the most efficacious anti‐cancer agents prescribed for a variety of solid tumors. However, CIS‐induced kidney injury (CIKI) remains a clinical challenge. The Organic Cation Transporter 2 (OCT2) is an uptake transporter predominantly expressed in the kidney proximal tubule cells. OCT2 is responsible for the cellular uptake of CIS by kidney cells. Our study aims to evaluate and quantify the in vitro renotoxicity effect of CIS and the reno‐protective effect of cimetidine (CIM), an OCT2 inhibitor, against CIKI. Methods Human renal proximal tubular epithelial cells, SA7K, were exposed for 72 hours to a range of concentrations of CIS (1–100 μM), CIM (0.1–2 mM), or to at least 12 different combinations of the two drugs. The inhibition of cellular viability was measured at 0, 12, 24, 48, and 72 hours using a CCK‐8 cellular viability kit. CIKI was captured with CIS stimulation of apoptosis in SA7K cells. CIM action on SA7K cells was fixed to the control (no treatment) baseline value. The combination of CIM with CIS was characterized with a competitive antagonism model using the Gaddum equation. Mathematical modeling was performed using Monolix (2016R1). All estimated parameters were determined as mean±SE. Results A dose‐dependent pattern in CIS toxicity on SA7K cells and CIM protection from CIKI is observed. The first‐order rate constant for SA7K cells death was estimated at 0.0047±0.00024 h −1 . The maximal effect of CIS on CIKI (S max ) was determined at 0.07±0.0064 h −1 , while CIS concentration inducing 50% of S max was estimated at 70.3±10.5 μM. The concentration of CIM leading to 50% of S max was determined at 486.3±69.8 μM. All time course profiles of cell viability responses to the single agents and combinations of CIS with CIM were described with our developed models. Conclusions The combination of CIM with CIS was successfully evaluated in vitro . The competitive antagonism model adequately captured the reno‐protective effects of CIM against CIKI. Further studies are in progress to investigate the molecular mechanisms underlying the beneficial effects of CIM on CIKI. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .