JBP485 attenuates vancomycin-induced nephrotoxicity by regulating the expressions of organic anion transporter (Oat) 1, Oat3, organic cation transporter 2 (Oct2), multidrug resistance-associated protein 2 (Mrp2) and P-glycoprotein (P-gp) in rats

Hydrochlorothiazide (HCTZ) is the most widely used thiazide diuretic for the treatment of hypertension either alone or in combination with other antihypertensives. HCTZ is mainly cleared by the kidney via tubular secretion, but the underlying molecular mechanisms are unclear. Using cells stably expressing major renal organic anion and cation transporters [human organic anion transporter 1 (hOAT1), human organic anion transporter 3 (hOAT3), human organic cation transporter 2 (hOCT2), human multidrug and toxin extrusion 1 (hMATE1), and human multidrug and toxin extrusion 2-K (hMATE2-K)], we found that HCTZ interacted with both organic cation and anion transporters. Uptake experiments further showed that HCTZ is transported by hOAT1, hOAT3, hOCT2, and hMATE2-K but not by hMATE1. Detailed kinetic analysis coupled with quantification of membrane transporter proteins by targeted proteomics revealed that HCTZ is an excellent substrate for hOAT1 and hOAT3. The apparent affinities ( Km) for hOAT1 and hOAT3 were 112 ± 8 and 134 ± 13 μM, respectively, and the calculated turnover numbers ( kcat) were 2.48 and 0.79 s−1, respectively. On the other hand, hOCT2 and hMATE2-K showed much lower affinity for HCTZ. The calculated transport efficiency ( kcat/ Km) at the single transporter level followed the rank order of hOAT1> hOAT3 > hOCT2 and hMATE2-K, suggesting a major role of organic anion transporters in tubular secretion of HCTZ. In vitro inhibition experiments further suggested that HCTZ is not a clinically relevant inhibitor for hOAT1 or hOAT3. However, strong in vivo inhibitors of hOAT1/3 may alter renal secretion of HCTZ. Together, our study elucidated the molecular mechanisms underlying renal handling of HCTZ and revealed potential pathways involved in the disposition and drug-drug interactions for this important antihypertensive drug in the kidney.

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Multiple Drug Transporters Are Involved in Renal Secretion of Entecavir

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00986-16 ◽

2016 ◽

Vol 60 (10) ◽

pp. 6260-6270 ◽

Cited By ~ 27

Author(s):

Xi Yang ◽

Zhiyuan Ma ◽

Sisi Zhou ◽

Yayun Weng ◽

Hongmei Lei ◽

...

Keyword(s):

Multidrug Resistance ◽

Organic Cation ◽

Organic Anion ◽

Organic Anion Transporter ◽

Multiple Drug ◽

Renal Secretion ◽

Renal Tubular Cells ◽

Anion Transporter ◽

Chronic Hepatitis B Virus ◽

In Cells

ABSTRACTEntecavir (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 μM) 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.

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Cisplatin induces renal expression of P-glycoprotein and canalicular multispecific organic anion transporter

AJP Renal Physiology ◽

10.1152/ajprenal.1999.277.6.f832 ◽

1999 ◽

Vol 277 (6) ◽

pp. F832-F840 ◽

Cited By ~ 11

Author(s):

Michel Demeule ◽

Mathieu Brossard ◽

Richard Béliveau

Keyword(s):

Chemotherapeutic Agent ◽

Organic Anion ◽

Organic Anion Transporter ◽

Rat Tissues ◽

Glycoprotein P ◽

P Glycoprotein ◽

Anion Transporter ◽

Renal Brush Border Membranes ◽

Renal Expression ◽

Renal Brush Border

The expression of two members of the ATP-binding cassette family of transport proteins, P-glycoprotein (P-gp) and the canalicular multispecific organic anion transporter (cMOAT or Mrp2), was evaluated in renal brush-border membranes (BBM) and various rat tissues after cisplatin treatment. One administration of cisplatin (5 mg/kg) increased P-gp expression by >200–300% in renal BBM and in crude membranes from liver and intestine. The increase in P-gp expression in the kidney was also detected in photolabeling experiments, suggesting the induction of functional P-gp. cMOAT expression was increased by >10-fold in renal BBM after cisplatin administration, although it had no effect on liver cMOAT expression. The increase in the levels of both proteins was maximal at 2 days after cisplatin treatment and lasted for at least 8 days. These results indicate that a single administration of cisplatin induces overexpression of P-gp and cMOAT in specific tissues. This may be of significant relevance to the design of clinical trials using cisplatin as a single chemotherapeutic agent or in combination with other drugs.

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Delineating the Contribution of Secretory Transporters in the Efflux of Etoposide Using Madin-Darby Canine Kidney (MDCK) Cells Overexpressing P-Glycoprotein (Pgp), Multidrug Resistance-Associated Protein (MRP1), and Canalicular Multispecific Organic Anion Transporter (cMOAT)

Drug Metabolism and Disposition ◽

10.1124/dmd.30.4.457 ◽

2002 ◽

Vol 30 (4) ◽

pp. 457-463 ◽

Cited By ~ 65

Author(s):

Ailan Guo ◽

William Marinaro ◽

Peidi Hu ◽

Patrick J. Sinko

Keyword(s):

Multidrug Resistance ◽

Mdck Cells ◽

Organic Anion ◽

Organic Anion Transporter ◽

Madin Darby Canine Kidney ◽

P Glycoprotein ◽

Anion Transporter ◽

Darby Canine Kidney ◽

Canine Kidney

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Sex Differences in the mRNA, Protein, and Functional Expression of Organic Anion Transporter (Oat) 1, Oat3, and Organic Cation Transporter (Oct) 2 in Rabbit Renal Proximal Tubules

Journal of Pharmacology and Experimental Therapeutics ◽

10.1124/jpet.105.094979 ◽

2005 ◽

Vol 316 (2) ◽

pp. 743-752 ◽

Cited By ~ 39

Author(s):

Carlotta E. Groves ◽

Wendy B. Suhre ◽

Nathan J. Cherrington ◽

Stephen H. Wright

Keyword(s):

Sex Differences ◽

Organic Cation ◽

Organic Anion ◽

Organic Cation Transporter ◽

Functional Expression ◽

Proximal Tubules ◽

Organic Anion Transporter ◽

Renal Proximal Tubules ◽

Anion Transporter

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Interaction of Ethambutol with Human Organic Cation Transporters of the SLC22 Family Indicates Potential for Drug-Drug Interactions during Antituberculosis Therapy

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01255-13 ◽

2013 ◽

Vol 57 (10) ◽

pp. 5053-5059 ◽

Cited By ~ 17

Author(s):

Xiaolei Pan ◽

Li Wang ◽

Dirk Gründemann ◽

Douglas H. Sweet

Keyword(s):

Drug Interactions ◽

Organic Cation ◽

Organic Anion ◽

Organic Cation Transporter ◽

Significant Inhibition ◽

Organic Anion Transporter ◽

Pharmacokinetic Studies ◽

Antituberculosis Therapy ◽

Anion Transporter

ABSTRACTAccording to the 2012 WHO global tuberculosis (TB) report (http://apps.who.int/iris/bitstream/10665/75938/1/9789241564502_eng.pdf), the death rate for tuberculosis was over 1.4 million patients in 2011, with ∼9 million new cases diagnosed. Moreover, the frequency of comorbidity with human immunodeficiency virus (HIV) and with diabetes is on the rise, increasing the risk of these patients for experiencing drug-drug interactions (DDIs) due to polypharmacy. Ethambutol is considered a first-line antituberculosis drug. Ethambutol is an organic cation at physiological pH, and its major metabolite, 2,2′-(ethylenediimino)dibutyric acid (EDA), is zwitterionic. Therefore, we assessed the effects of ethambutol and EDA on the function of human organic cation transporter 1 (hOCT1), hOCT2, and hOCT3 and that of EDA on organic anion transporter 1 (hOAT1) and hOAT3. Potent inhibition of hOCT1- and hOCT2-mediated transport by ethambutol (50% inhibitory concentration [IC50] = 92.6 ± 10.9 and 253.8 ± 90.8 μM, respectively) was observed. Ethambutol exhibited much weaker inhibition of hOCT3 (IC50= 4.1 ± 1.6 mM); however, significant inhibition (>80%) was observed at physiologically relevant concentrations in the gastrointestinal (GI) tract after oral dosing. EDA failed to exhibit any inhibitory effects that warranted further investigation. DDI analysis indicated a strong potential for ethambutol interaction on hOCT1 expressed in enterocytes and hepatocytes and on hOCT3 in enterocytes, which would alter absorption, distribution, and excretion of coadministered cationic drugs, suggesting thatin vivopharmacokinetic studies are necessary to confirm drug safety and efficacy. In particular, TB patients with coexisting HIV or diabetes might experience significant DDIs in situations of coadministration of ethambutol and clinical therapeutics known to be hOCT1/hOCT3 substrates (e.g., lamivudine or metformin).

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