scholarly journals In Vitro Inhibition of Renal OCT2 and MATE1 Secretion by Antiemetic Drugs

2021 ◽  
Vol 22 (12) ◽  
pp. 6439
Author(s):  
Blessy George ◽  
Xia Wen ◽  
Edgar A. Jaimes ◽  
Melanie S. Joy ◽  
Lauren M. Aleksunes
Keyword(s):  
Organic Cation ◽  
Mdck Cells ◽  
Organic Cation Transporter ◽  
Hek293 Cells ◽  
Intracellular Accumulation ◽  
Renal Secretion ◽  
Transcellular Transport ◽  
Antiemetic Drugs ◽  
Organic Cation Transporter 2

The organic cation transporter 2 (OCT2) and multidrug and toxin extrusion protein 1 (MATE1) mediate the renal secretion of drugs. Recent studies suggest that ondansetron, a 5-HT3 antagonist drug used to prevent nausea and vomiting, can inhibit OCT2- and MATE1-mediated transport. The purpose of this study was to test the ability of five 5-HT3 antagonist drugs to inhibit the OCT2 and MATE1 transporters. The transport of the OCT2/MATE1 probe substrate ASP+ was assessed using two models: (1) HEK293 kidney cells overexpressing human OCT2 or MATE1, and (2) MDCK cells transfected with human OCT2 and MATE1. In HEK293 cells, the inhibition of ASP+ uptake by OCT2 listed in order of potency was palonosetron (IC50: 2.6 μM) > ondansetron > granisetron > tropisetron > dolasetron (IC50: 85.4 μM) and the inhibition of ASP+ uptake by MATE1 in order of potency was ondansetron (IC50: 0.1 μM) > palonosetron = tropisetron > granisetron > dolasetron (IC50: 27.4 μM). Ondansetron (0.5–20 μM) inhibited the basolateral-to-apical transcellular transport of ASP+ up to 64%. Higher concentrations (10 and 20 μM) of palonosetron, tropisetron, and dolasetron similarly reduced the transcellular transport of ASP+. In double-transfected OCT2-MATE1 MDCK cells, ondansetron at concentrations of 0.5 and 2.5 μM caused significant intracellular accumulation of ASP+. Taken together, these data suggest that 5-HT3 antagonist drugs may inhibit the renal secretion of cationic drugs by interfering with OCT2 and/or MATE1 function.

Wedelolactone protects against cisplatin-induced nephrotoxicity in mice via inhibition of organic cation transporter 2

2021 ◽  
pp. 096032712110479
Author(s):  
Guangju Wang ◽  
Yajuan Bi ◽  
Hui Xiong ◽  
Tongwei Bo ◽  
Lifeng Han ◽  
...  
Keyword(s):  
Natural Compound ◽  
Organic Cation ◽  
Kidney Injury ◽  
Organic Cation Transporter ◽  
Competitive Inhibitor ◽  
Hek293 Cells ◽  
Cytotoxicity Studies ◽  
Organic Cation Transporter 2 ◽  
Uptake Assay ◽  
Noncompetitive Inhibitor

The balance of cisplatin uptake and efflux, mediated mainly by organic cation transporter 2 (OCT2) and multidrug and toxin extrusion 1 (MATE1), respectively, determines the renal accumulation and nephrotoxicity of cisplatin. Using transporter-mediated cellular uptake assay, we identified wedelolactone (WEL), a medicinal plant-derived natural compound, is a competitive inhibitor of OCT2 and a noncompetitive inhibitor of MATE1. Wedelolactone showed a selectivity to inhibit OCT2 rather than MATE1. Cytotoxicity studies revealed that wedelolactone alleviated cisplatin-induced cytotoxicity in OCT2-overexpressing HEK293 cells, whereas it did not alter the cytotoxicity of cisplatin in various cancer cell lines. Additionally, wedelolactone altered cisplatin pharmacokinetics, reduced kidney accumulation of cisplatin, and ameliorated cisplatin-induced acute kidney injury in the Institute of Cancer Research mice. In conclusion, these findings suggest a translational potential of WEL as a natural therapy for preventing cisplatin-induced nephrotoxicity and highlight the need for drug–drug interaction investigations of WEL with other treatments which are substrates of OCT2 and/or MATE1.

scholarly journals Atenolol Renal Secretion Is Mediated by Human Organic Cation Transporter 2 and Multidrug and Toxin Extrusion Proteins

2015 ◽  
Vol 43 (12) ◽  
pp. 1872-1881 ◽  
Author(s):  
Jia Yin ◽  
Haichuan Duan ◽  
Yoshiyuki Shirasaka ◽  
Bhagwat Prasad ◽  
Joanne Wang
Keyword(s):  
Organic Cation ◽  
Organic Cation Transporter ◽  
Renal Secretion ◽  
Organic Cation Transporter 2 ◽  
Toxin Extrusion

scholarly journals Substrate-Dependent Trans-Stimulation of Organic Cation Transporter 2 Activity

2021 ◽  
Vol 22 (23) ◽  
pp. 12926
Author(s):  
Charles R. Lefèvre ◽  
Marc Le Vée ◽  
Sophie Gaubert ◽  
Elodie Jouan ◽  
Arnaud Bruyere ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Drug Toxicity ◽  
Organic Cation ◽  
Molecular Descriptors ◽  
Organic Cation Transporter ◽  
Hek293 Cells ◽  
Ic50 Values ◽  
Organic Cation Transporter 2 ◽  
Low Sensitivity ◽  
Stimulation Of

The search of substrates for solute carriers (SLCs) constitutes a major issue, owing notably to the role played by some SLCs, such as the renal electrogenic organic cation transporter (OCT) 2 (SLC22A2), in pharmacokinetics, drug–drug interactions and drug toxicity. For this purpose, substrates have been proposed to be identified by their cis-inhibition and trans-stimulation properties towards transporter activity. To get insights on the sensitivity of this approach for identifying SLC substrates, 15 various exogenous and endogenous OCT2 substrates were analysed in the present study, using 4-(4-(dimethylamino)styryl)-N-methylpyridinium iodide (DiASP) as a fluorescent OCT2 tracer substrate. All OCT2 substrates cis-inhibited DiASP uptake in OCT2-overexpressing HEK293 cells, with IC50 values ranging from 0.24 µM (for ipratropium) to 2.39 mM (for dopamine). By contrast, only 4/15 substrates, i.e., acetylcholine, agmatine, choline and metformin, trans-stimulated DiASP uptake, with a full suppression of the trans-stimulating effect of metformin by the reference OCT2 inhibitor amitriptyline. An analysis of molecular descriptors next indicated that trans-stimulating OCT2 substrates exhibit lower molecular weight, volume, polarizability and lipophilicity than non-trans-stimulating counterparts. Overall, these data indicated a rather low sensitivity (26.7%) of the trans-stimulation assay for identifying OCT2 substrates, and caution with respect to the use of such assay may therefore be considered.

scholarly journals Inhibition of the Hepatic Uptake of 99mTc-Tetrofosmin Using an Organic Cation Transporter Blocker

Pharmaceutics ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1073
Author(s):  
Kodai Nishi ◽  
Masato Kobayashi ◽  
Minori Kikuchi ◽  
Asuka Mizutani ◽  
Yuka Muranaka ◽  
...  
Keyword(s):  
Organic Cation ◽  
Organic Anion ◽  
Specific Inhibitor ◽  
In Vitro Study ◽  
Organic Cation Transporter ◽  
Vitro Study ◽  
Hek293 Cells ◽  
Emission Computed Tomography ◽  
99Mtc Tetrofosmin

The accumulation of high levels of 99mTc-tetrofosmin (99mTc-TF) in the hepatobiliary system can lead to imaging artifacts and interference with diagnosis. The present study investigated the transport mechanisms of 99mTc-TF and attempted to apply competitive inhibition using a specific inhibitor to reduce 99mTc-TF hepatic accumulation. In this in vitro study, 99mTc-TF was incubated in HEK293 cells expressing human organic anion transporting polypeptide 1B1 (OATP1B1), OATP1B3, OATP2B1, organic anion transporter 2 (OAT2), organic cation transporter 1 (OCT1), OCT2, and Na+-taurocholate cotransporting polypeptide with or without each specific inhibitor to evaluate the contribution of each transporter to 99mTc-TF transportation. In vivo studies, dynamic planar imaging, and single photon emission computed tomography (SPECT) experiments with rats were performed to observe alterations to 99mTc-TF pharmacokinetics using cimetidine (CMT) as an OCT1 inhibitor. Time–activity curves in the liver and heart were acquired from dynamic data, and the 99mTc-TF uptake ratio was calculated from SPECT. From the in vitro study, 99mTc-TF was found to be transported by OCT1 and OCT2. When CMT-preloaded rats and control rats were compared, the hepatic accumulation of the 99mTc-TF was reduced, and the time to peak heart count shifted to an earlier stage. The hepatic accumulation of 99mTc-TF was markedly suppressed, and the heart-to-liver ratio increased 1.6-fold. The pharmacokinetics of 99mTc-TF were greatly changed by OCT1 inhibitor. Even in humans, the administration of OCT1 inhibitor before cardiac SPECT examination may reduce 99mTc-TF hepatic accumulation and contribute to the suppression of artifacts and the improvement of SPECT image quality.

Abstract 14035: Renal Tubular Secretion and Cardiac Distribution of Dofetilide is Dependent on MATE1 Function

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Muhammad Erfan Uddin ◽  
Yan Jin ◽  
Alice A Gibson ◽  
Ingrid M Bonilla ◽  
Cynthia A Carnes ◽  
...  
Keyword(s):  
Organic Cation ◽  
Tubular Secretion ◽  
Hek293 Cells ◽  
Delayed Rectifier ◽  
Organic Cation Transporters ◽  
Wild Type ◽  
Renal Tubular Secretion ◽  
Cation Transporters ◽  
Renal Tubular

Introduction: Dofetilide is a delayed rectifier potassium channel inhibitor used to treat patients with atrial fibrillation and flutter, and its use is associated with a risk of QT prolongation and Torsades de Pointes . The mechanisms involved in dofetilide’s renal tubular secretion and its uptake into cardiomyocytes remain unknown. Previously reported drug-drug interaction (DDI) studies suggest the involvement of organic cation transporters. Here, we investigated the contribution of organic cation transporters (OCT2 and MATE1) to the pharmacokinetics of dofetilide to gain insight into its DDI potential. Hypothesis: Based on known DDIs with dofetilide, we hypothesize that OCT2 and/or MATE1 play a key role in the inter-individual variability in pharmacokinetics and pharmacodynamics of dofetilide. Methods: In vitro and ex vivo transport kinetics of dofetilide were determined in HEK293 cells stably transfected with OCT2 or MATE1, and in isolated cardiomyocytes, respectively. In vivo studies were performed in wild-type, OCT2-, and MATE1-deficient mice (n=5) receiving dofetilide (5 mg/kg, p.o., 2.5 mg/kg, i.v.), with or without several contraindicated drugs. Dofetilide concentrations in plasma and urine were determined by UPLC-MS/MS. Results: In vitro studies demonstrated that dofetilide is a good substrate of MATE1 but not OCT2. Deficiency of MATE1 was associated with increased plasma concentrations of dofetilide and with a significantly reduced urinary excretion (3-fold in females and 5-fold in males, respectively). Dofetilide accumulation in cardiomyocytes was increased by 2-fold in MATE1-deficient females, and pre-incubation with the MATE1 inhibitor cimetidine significantly reduced dofetilide uptake in wild-type cardiomyocytes. Several contraindicated drugs listed in the dofetilide prescribing information, including cimetidine, ketoconazole, increased dofetilide plasma exposure in wild-type mice by >2.8-fold. Conclusion: Renal secretion of dofetilide is mediated by MATE1 and is highly sensitive to inhibition by many widely used prescription drugs that can cause clinically relevant DDIs. Deficiency of MATE1 also increases accumulation in the heart which may contribute to individual variation in response to dofetilide.

Different Affinities of Inhibitors to the Outwardly and Inwardly Directed Substrate Binding Site of Organic Cation Transporter 2

2003 ◽  
Vol 64 (5) ◽  
pp. 1037-1047 ◽  
Author(s):  
Christopher Volk ◽  
Valentin Gorboulev ◽  
Thomas Budiman ◽  
Georg Nagel ◽  
Hermann Koepsell
Keyword(s):  
Binding Site ◽  
Organic Cation ◽  
Substrate Binding ◽  
Organic Cation Transporter ◽  
Substrate Binding Site ◽  
Organic Cation Transporter 2
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