Molecular Mechanism of Renal Tubular Secretion of the Antimalarial Drug Chloroquine

Müller, Fabian; König, Jörg; Glaeser, Hartmut; Schmidt, Ingrid; Zolk, Oliver; Fromm, Martin F.; Maas, Renke

doi:10.1128/aac.01835-10

Cited by 60 publications

(50 citation statements)

References 40 publications

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“…The major new findings of our investigations are the following: (1) Trimethoprim inhibits OCT2-, MATE1-, and MATE2-K-dependent transport of both metformin and NMN in vitro. Our data are in line with previous reports investigating in vitro inhibition of OCT2-and MATE1-dependent metformin transport by trimethoprim and are to the best of our knowledge the first to show that trimethoprim also inhibits NMN transport [19,21]. We estimate that mean unbound trimethoprim trough and peak plasma concentrations were ∼4 and 9 μM, respectively, in the healthy volunteers of our study (assuming f u =0.6).…”

Section: Discussionsupporting

confidence: 93%

“…**p<0.01 vs. phase A/day 4 preferential MATE1 inhibition; for NMN: preferential MATE2-K inhibition) compared to inhibition of basolateral uptake via OCT2. Our previously reported IC 50 value for inhibition of MATE1-mediated metformin transport by trimethoprim [21] is in very good agreement with the respective K i value we determined in the present experiments (6.2 vs 6.3 μM). We previously reported that trimethoprim also preferentially inhibits MATE2-K-mediated lamivudine transport (IC 50 =0.66 μM) compared to OCT2-mediated lamivudine transport (IC 50 =13.2 μM) [18].…”

Section: Discussionsupporting

confidence: 91%

“…In vitro experiments Uptake experiments were performed with previously established cell lines as described elsewhere [18,21,22]. Briefly, HEK cells stably overexpressing OCT1, OCT2, or MATE1 or transiently overexpressing MATE2-K or the respective empty vector control cells (HEK-Co) were seeded in poly-D-lysine-coated (poly-D-lysine hydrobromide, PDL, 0.1 mg/ml, Sigma-Aldrich, Taufkirchen, Germany) 12-well plates (Greiner Bio-One, Frickenhausen, Germany).…”

Section: Methodsmentioning

confidence: 99%

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N1-methylnicotinamide as an endogenous probe for drug interactions by renal cation transporters: studies on the metformin–trimethoprim interaction

Müller

Pontones

Renner

et al. 2014

Eur J Clin Pharmacol

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118

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Section: Discussionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 91%

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

N1-methylnicotinamide as an endogenous probe for drug interactions by renal cation transporters: studies on the metformin–trimethoprim interaction

Müller

Pontones

Renner

et al. 2014

Eur J Clin Pharmacol

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118

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“…All of the MDCK cell lines were cultured in Dulbecco's modified Eagle's medium (DMEM) supplemented with 10% heat-inactivated fetal bovine serum (FBS). Double-transfected MDCKII cell lines stably expressing human OCT1 or OCT2 and MATE1 transporters (MDCK-OCT1-MATE1 and MDCK-OCT2-MATE1), as well as the respective monotransfected cells (MDCK-OCT1, MDCK-OCT2, and MDCK-MATE1) and control vector cells (MDCK-Co), were established and characterized as described previously (17,21,22). Cells were cultured in MEM containing 10% heat-inactivated FBS.…”

Section: Methodsmentioning

confidence: 99%

Role of ABC and Solute Carrier Transporters in the Placental Transport of Lamivudine

Čečková

Reznicek

Ptackova

et al. 2016

Antimicrob Agents Chemother

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Lamivudine is one of the antiretroviral drugs of choice for the prevention of mother-to-child transmission (MTCT) in HIV-positive women. In this study, we investigated the relevance of drug efflux transporters P-glycoprotein (P-gp) (MDR1 [ABCB1]), BCRP (ABCG2), MRP2 (ABCC2), and MATE1 (SLC47A1) for the transmembrane transport and transplacental transfer of lamivudine. We employed in vitro accumulation and transport experiments on MDCK cells overexpressing drug efflux transporters, in situ-perfused rat term placenta, and vesicular uptake in microvillous plasma membrane (MVM) vesicles isolated from human term placenta. MATE1 significantly accelerated lamivudine transport in MATE1-expressing MDCK cells, whereas no transporter-driven efflux of lamivudine was observed in MDCK-MDR1, MDCK-MRP2, and MDCK-BCRP monolayers. MATE1-mediated efflux of lamivudine appeared to be a low-affinity process (apparent K m of 4.21 mM and V max of 5.18 nmol/mg protein/min in MDCK-MATE1 cells). Consistent with in vitro transport studies, the transplacental clearance of lamivudine was not affected by P-gp, BCRP, or MRP2. However, lamivudine transfer across dually perfused rat placenta and the uptake of lamivudine into human placental MVM vesicles revealed pH dependency, indicating possible involvement of MATE1 in the fetal-to-maternal efflux of the drug. To conclude, placental transport of lamivudine does not seem to be affected by P-gp, MRP2, or BCRP, but a pH-dependent mechanism mediates transport of lamivudine in the fetal-to-maternal direction. We suggest that MATE1 might be, at least partly, responsible for this transport.

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“…The transcellular transport studies were performed as reported previously (22). Cells were seeded on transwell inserts (0.4 m, diameter of 12 mm) at a density of 2 ϫ 10 5 cells per insert for MDCK-hOCT2-hMATE1, MDCK-hOCT2, and MDCKhMATE1 and at 1 ϫ 10 5 cells per insert for mock-transfected cells to unify protein concentrations for different amounts of cell growth.…”

mentioning

confidence: 99%

Multiple Drug Transporters Are Involved in Renal Secretion of Entecavir

Yang

Zhou

et al. 2016

Antimicrob Agents Chemother

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Entecavir (ETV) is a first-line antiviral agent for the treatment of chronic hepatitis B virus infection. Renal excretion is the major elimination path of ETV, in which tubular secretion plays the key role. However, the secretion mechanism has not been clarified. We speculated that renal transporters mediated the secretion of ETV. Therefore, the aim of our study was to elucidate which transporters contribute to the renal disposition of ETV. Our results revealed that ETV (50 M) remarkably reduced the accumulation of probe substrates in MDCK cells stably expressing human multidrug and toxin efflux extrusion proteins (hMATE1/2-K), organic cation transporter 2 (hOCT2), and carnitine/organic cation transporters (hOCTNs) and increased the substrate accumulation in cells transfected with multidrug resistance-associated protein 2 (hMRP2) or multidrug resistance protein 1 (hMDR1). Moreover, ETV was proved to be a substrate of the above-described transporters. In transwell studies, the transport of ETV in MDCK-hOCT2-hMATE1 showed a distinct directionality from BL (hOCT2) to AP (hMATE1), and the cellular accumulation of ETV in cells expressing hMATE1 was dramatically lower than that of the mock-treated cells. The accumulation of ETV in mouse primary renal tubular cells was obviously affected by inhibitors of organic anion transporter 1/3 (Oat1/3), Oct2, Octn1/2, and Mrp2. Therefore, the renal uptake of ETV is likely mediated by OAT1/3 and OCT2 while the efflux is mediated by MATEs, MDR1, and MRP2, and OCTN1/2 may participate in both renal secretion and reabsorption. C hronic hepatitis B virus (HBV) infection, with a high rate of morbidity, is one of the most important health problems worldwide. It is a major risk factor for cirrhosis and liver cancer (1). Entecavir (ETV) is a novel and highly selective deoxyguanosine analog with a high antiviral efficacy and a high genetic barrier to viral resistance (2). Since ETV was approved in 2005 by the U.S. FDA, it has been unanimously recommended as the fist-line antiviral agent for treatment of chronic HBV infection by global hepatology scientific societies, such as the American Association for the Study of Liver Diseases and the European Association for the Study of the Liver (3, 4).It was reported that about 73% of orally dosed ETV was eliminated in urine in an unchanged form. The renal clearance of ETV is independent of the dose and ranged from 360 to 471 ml/min in healthy volunteers, which is much greater than the glomerular filtration rate (GFR; 120 to 130 ml/min for normal humans) (5, 6), suggesting that tubular secretion accounts for the major part of the urinary excretion of ETV. Therefore, it is speculated that transporters expressed on the proximal tubular cells are involved in the process of tubular secretion of ETV. Furthermore, ETV is a hydrophilic weak base with a pK a value of 10.5 (Ͼ99% of ETV is positively charged at pH 7.4) and a logD value of Ϫ1.1 (pH 4 to 10), which implies that ETV is unlikely to penetrate the cell membrane by passive diffusion. Thus, transpor...

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Molecular Mechanism of Renal Tubular Secretion of the Antimalarial Drug Chloroquine

Abstract: The antimalarial drug chloroquine is eliminated to a significant extent by renal tubular secretion. The molecular mechanism of renal chloroquine secretion remains unknown. We hypothesized that organic cation transporter 2 (OCT2) and multidrug and toxin extrusion protein 1 (

Cited by 60 publications

References 40 publications

N1-methylnicotinamide as an endogenous probe for drug interactions by renal cation transporters: studies on the metformin–trimethoprim interaction

N1-methylnicotinamide as an endogenous probe for drug interactions by renal cation transporters: studies on the metformin–trimethoprim interaction

Role of ABC and Solute Carrier Transporters in the Placental Transport of Lamivudine

Multiple Drug Transporters Are Involved in Renal Secretion of Entecavir

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