Organic Cation Transporter OCTs (SLC22) and MATEs (SLC47) in the Human Kidney

Motohashi, Hideyuki; Inui, Ken Ichi

doi:10.1208/s12248-013-9465-7

Cited by 167 publications

(144 citation statements)

References 52 publications

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“…Schematic overview of the most important transporters involved in the absorption, hepatic uptake, and excretion of metformin (11,15,(40)(41)(42)(43).…”

Section: Figmentioning

confidence: 99%

Moxifloxacin Is a Potent In Vitro Inhibitor of OCT- and MATE-Mediated Transport of Metformin and Ethambutol

Brake

Heuvel

Buaben

et al. 2016

Antimicrob Agents Chemother

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c It is largely unknown if simultaneous administration of tuberculosis (TB) drugs and metformin leads to drug-drug interactions (DDIs). Disposition of metformin is determined by organic cation transporters (OCTs) and multidrug and toxin extrusion proteins (MATEsT uberculosis (TB) remains a leading cause of morbidity and mortality in developing countries, claiming over a million lives annually (1). Treatment of TB requires long and intensive combination drug therapy, which can be complicated by the presence of concurrent diseases. The noncommunicable disease diabetes mellitus (DM) impacts TB with increasing magnitude (2, 3). At the moment, an estimated 15% of TB cases can be attributed to DM (3).Patients with DM have three times the risk of developing active TB compared to nondiabetics (3, 4), probably because of impaired host defenses. In addition, patients with TB and DM show a worse response to TB treatment than patients with TB alone and thus face a higher risk of TB treatment failure, relapse after cure, and death (5). The impact of DM will only increase further due to the rising prevalence of DM, especially in countries where TB is endemic. On the other hand, DM management is hampered by TB treatment. The TB drug rifampin possibly affects blood glucose itself and induces hyperglycemia by augmenting intestinal absorption of glucose or reducing insulin sensitivity (6, 7).Metformin is the first-choice antihyperglycemic drug to treat diabetes mellitus type 2. It is affordable and may be advantageous when combined with rifampin, as it is not metabolized. Metformin lowers both basal and postprandial plasma glucose (8) by inhibiting the production of hepatic glucose, reducing intestinal glucose absorption, and improving glucose uptake and utilization (9). Interestingly, recent data show that metformin also inhibits the intracellular growth of M. tuberculosis, restricts disease immunopathology, and augments the efficacy of conventional TB drugs. It has even been suggested as a possible adjunctive to standard TB treatment in nondiabetic TB patients (10).Metformin is eliminated unchanged into the urine with a halflife of approximately 5 h (11). Over a range of renal functions, the mean renal clearance in the population is approximately 4 times greater than that of creatinine, indicating that tubular secretion is the most important route of elimination (11). The oral absorption, hepatic uptake, and renal excretion of metformin are largely mediated by membrane transporters of the solute carrier (SLC) family, namely, organic cation transporters 1, 2, and 3 (OCT1, OCT2, and OCT3) and multidrug and toxin extrusion proteins 1 and 2K (MATE1 and MATE2K) ( Fig. 1) (11, 12). Genetic polymorphisms in these transporter genes explain at least some of the variability observed in metformin pharmacokinetics and drug responses (11). Furthermore, from studies of humans and mice, we know that inhibitors of OCTs and MATEs can alter the disposition of concomitantly administered organic cations, increasing

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“…Schematic overview of the most important transporters involved in the absorption, hepatic uptake, and excretion of metformin (11,15,(40)(41)(42)(43).…”

Section: Figmentioning

confidence: 99%

Moxifloxacin Is a Potent In Vitro Inhibitor of OCT- and MATE-Mediated Transport of Metformin and Ethambutol

Brake

Heuvel

Buaben

et al. 2016

Antimicrob Agents Chemother

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“…Besides glomerular filtration, circulating drugs are actively secreted by carrier-mediated pathways in the renal proximal tubules. In humans, secretion of organic cation (OC) drugs is primarily accomplished by basolateral uptake via the electrogenic human organic cation transporter 2 (hOCT2) followed by apical efflux via the proton/OC exchangers human multidrug and toxin extrusion proteins 1 and 2-K (hMATE1 and 2-K) (Li et al, 2006;Giacomini et al, 2010;Morrissey et al, 2013;Motohashi and Inui, 2013). Anionic drug molecules, on the other hand, are generally first transported into tubular cells by the basolateral organic anion transporters 1 and 3 (hOAT1 and 3) and then effluxed into the lumen by apical transporters such as the multidrug resistance-associated proteins 2 and 4 (Li et al, 2006;Giacomini et al, 2010;Morrissey et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Impact of Substrate-Dependent Inhibition on Renal Organic Cation Transporters hOCT2 and hMATE1/2-K-Mediated Drug Transport and Intracellular Accumulation

Yin

Duan

Wang

2016

J Pharmacol Exp Ther

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Renal transporter-mediated drug-drug interactions (DDIs) are of significant clinical concern, as they can adversely impact drug disposition, efficacy, and toxicity. Emerging evidence suggests that human renal organic cation transporter 2 (hOCT2) and multidrug and toxin extrusion proteins 1 and 2-K (hMATE1/2-K) exhibit substrate-dependent inhibition, but their impact on renal drug secretion and intracellular accumulation is unknown. Using metformin and atenolol as the probe substrates, we found that the classic inhibitors (e.g., cimetidine) of renal organic cation secretion were approximately 10-fold more potent for hOCT2 when atenolol was used, suggesting that atenolol is a more sensitive in vitro substrate for hOCT2 than metformin. In contrast, inhibition of hMATE1/2-K was influenced much less by the choice of substrate. Cimetidine is a much more potent inhibitor for hMATE1/2-K when metformin is the substrate but acts as an equally potent inhibitor of hOCT2 and hMATE1/2-K when atenolol is the substrate. Using hOCT2/hMATE1 doubletransfected Madin-Darby canine kidney cells, we evaluated the impact of substrate-dependent inhibition on hOCT2/hMATE1-mediated transepithelial flux and intracellular drug accumulation. At clinically relevant concentrations, cimetidine dose dependently inhibited basal-to-apical flux of atenolol and metformin but impacted their intracellular accumulation differently, indicating that substrate-dependent inhibition may shift the major substrate-inhibitor interaction site between apical and basolateral transporters. Cimetidine is effective only when applied to the basal compartment. Our findings revealed the complex and dynamic nature of substrate-dependent inhibition of renal organic cation drug transporters and highlighted the importance of considering substrate-dependent inhibition in predicting transporter-mediated renal drug interaction, accumulation, and toxicity.

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“…In human kidneys, circulating organic cations are first transported into renal tubular cells by the electrogenic basolateral organic cation transporter (hOCT) 2, which is driven by the inside negative membrane potential. Once inside the cells, organic cations are further secreted into the urine by the apical multidrug and toxin extrusion proteins (hMATE) 1 and 2-K, which are proton/ organic cation exchangers that use the inwardly directed proton gradient in the nephron to drive efflux (Motohashi and Inui, 2013). Organic anion drugs, on the other hand, are first transported into tubular cells by the basolateral organic anion transporters (hOATs) 1 and 3 (You, 2004;Burckhardt, 2012).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2015

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Atenolol is a b-blocker widely used in the treatment of hypertension. Atenolol is cleared predominantly by the kidney by both glomerular filtration and active secretion, but the molecular mechanisms involved in its renal secretion are unclear. Using a panel of human embryonic kidney cell lines stably expressing human organic cation transporter (hOCT) 1-3, human organic anion transporter (hOAT) 1, hOAT3, human multidrug and toxin extrusion protein (hMATE) 1, and hMATE2-K, we found that atenolol interacted with both organic cation and anion transporters. However, it is transported by hOCT1, hOCT2, hMATE1, and hMATE2-K, but not by hOCT3, hOAT1, and hOAT3. A detailed kinetic analysis coupled with absolute quantification of membrane transporter proteins by liquid chromatographytandem mass spectrometry revealed that atenolol is an excellent substrate for the renal transporters hOCT2, hMATE1, and hMATE2-K. The K m values for hOCT2, hMATE1, and hMATE2-K are 280 6 4, 32 6 5, and 76 6 14 mM, respectively, and the calculated turnover numbers are 2.76, 0.41, and 2.20 s 21 , respectively. To demonstrate unidirectional transepithelial transport of atenolol, we developed and functionally validated a hOCT2/hMATE1 double-transfected Madin-Darby canine kidney cell culture model. Transwell studies showed that atenolol transport in the basal (B)-to-apical (A) direction is 27-fold higher than in the A-to-B direction, whereas its B-to-A/A-to-B transport ratio was only 2 in the vectortransfected control cells. The overall permeability of atenolol in the B-to-A direction in hOCT2/hMATE1 cells was 44-fold higher than in control cells. Together, our data support that atenolol tubular secretion is mediated through the hOCT2/hMATEs secretion pathway and suggest a significant role of organic cation transporters in the disposition of an important antihypertensive drug.

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Organic Cation Transporter OCTs (SLC22) and MATEs (SLC47) in the Human Kidney

Cited by 167 publications

References 52 publications

Moxifloxacin Is a Potent In Vitro Inhibitor of OCT- and MATE-Mediated Transport of Metformin and Ethambutol

Moxifloxacin Is a Potent In Vitro Inhibitor of OCT- and MATE-Mediated Transport of Metformin and Ethambutol

Impact of Substrate-Dependent Inhibition on Renal Organic Cation Transporters hOCT2 and hMATE1/2-K-Mediated Drug Transport and Intracellular Accumulation

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

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