scholarly journals Molecular Mechanism of Renal Tubular Secretion of the Antimalarial Drug Chloroquine

2011 ◽  
Vol 55 (7) ◽  
pp. 3091-3098 ◽  
Author(s):  
Fabian Müller ◽  
Jörg König ◽  
Hartmut Glaeser ◽  
Ingrid Schmidt ◽  
Oliver Zolk ◽  
...  
Keyword(s):  
Vector Control ◽  
Molecular Mechanism ◽  
Antimalarial Drug ◽  
Organic Cation Transporter ◽  
Competitive Inhibitor ◽  
Tubular Secretion ◽  
Transcellular Transport ◽  
Cellular Accumulation ◽  
Renal Tubular Secretion ◽  
Renal Tubular

ABSTRACTThe 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 (MATE1), localized in the basolateral and luminal membranes of proximal tubule cells, respectively, are involved in chloroquine transport. The interaction of chloroquine with both transporters was investigated using single-transfected human embryonic kidney 293 (HEK293)-MATE1 cells in uptake experiments and single-transfected Madin-Darby canine kidney II (MDCK)-OCT2 and MDCK-MATE1 cells as well as double-transfected MDCK-OCT2-MATE1 cells grown as polarized monolayers on transwell filters. In HEK293-MATE1 cells, chloroquine competitively inhibited MATE1-mediated metformin uptake (Ki= 2.8 μM). Cellular accumulation of chloroquine was significantly lower (P< 0.001) and transcellular chloroquine transport was significantly increased (P< 0.001) in MDCK-MATE1 and MDCK-OCT2-MATE1 cells compared to vector control cells after basal addition of chloroquine (0.1 to 10 μM). In contrast, no difference in cellular accumulation or transcellular transport of chloroquine was observed between MDCK-OCT2 and vector control cells. In line with an oppositely directed proton gradient acting as a driving force for MATE1, basal-to-apical transport of chloroquine by MDCK-OCT2-MATE1 cells increased with decreasing apical pH from 7.8 to 6.0. Transcellular transport of chloroquine by MDCK-OCT2-MATE1 cells was inhibited by cimetidine, trimethoprim, and amitriptyline. Our data demonstrate that chloroquine is a substrate and potent competitive inhibitor of MATE1, whereas OCT2 seems to play no role in chloroquine uptake. Concomitantly administered MATE1 inhibitors are likely to modify the renal secretion of chloroquine.

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.

Renal tubular secretion of organic anions

1997 ◽  
Vol 25 (2-3) ◽  
pp. 217-230 ◽  
Author(s):  
William H. Dantzler ◽  
Stephen H. Wright
Keyword(s):  
Organic Anions ◽  
Tubular Secretion ◽  
Renal Tubular Secretion ◽  
Renal Tubular

Pharmacokinetic study of clofarabine: Oral bioavailability and the effect of cimetidine on renal clearance.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e13074-e13074
Author(s):  
Matthew Charles Foster ◽  
Parag Kumar ◽  
Christine Marie Walko ◽  
Anastasia Ivanova ◽  
Reginald Ewesuedo ◽  
...  
Keyword(s):  
Renal Clearance ◽  
Basolateral Membrane ◽  
Area Under The Curve ◽  
Organic Cation Transporter ◽  
Tubular Secretion ◽  
Time Data ◽  
Geometric Means ◽  
Human Trial ◽  
Organic Cation Transporter 2 ◽  
Renal Tubular

e13074 Background: Clofarabine (CLO) is a purine analog with activity in myeloid neoplasms. Its oral dosing has been based on an estimated bioavailability (F) of 49% from uncontrolled trials. Animal models suggest that CLO renal clearance (CL) may be impaired in the presence of inhibitors of organic cation transporter-2 (OCT2), which mediates transport across the renal tubular basolateral membrane. We conducted a pharmacokinetic (PK) study of CLO to determine F, and examine the effect of the OCT2 inhibitor, cimetidine (CIM) on intravenous (IV) CLO. Methods: Patients had: 1) untreated AML ≥ 60 years of age unsuited for standard induction, 2) relapsed or refractory AML, or 3) MDS after failure of ≥ 1 prior regimen. Treatment was: CLO 15 mg/m2 IV day 1, CLO 30 mg/m2 orally (PO) day 3, CLO 15 mg/m2 IV day 5 preceded by two doses of oral CIM, and CLO 30 mg/m2 PO on days 6 and 7. PK studies were obtained after CLO dosing on days 1, 3 and 5. For each dose, CLO plasma concentration was determined, and concentration-time data was analyzed by non-compartmental methods. F was determined for each patient. The geometric means of area under the curve (AUC), 0-∞, and CL for IV CLO administered after CIM doses were compared with AUC and CL for IV CLO administered without CIM. Results: Interim data for the first ten treated patients, with comparisons of PK parameters are shown in the table below. Conclusions: Using patients as their own controls, F of CLO is higher than previously estimated. AUC of CLO is increased and CL is decreased in the presence of CIM, likely owing to inhibition of OCT2-mediated renal tubular secretion. This study is the first human trial to suggest that CLO CL may be impaired in the presence of OCT2 inhibitors, such as cimetidine, trimethoprim, verapamil and nicotine. [Table: see text]

Renal tubular secretion and effects of furosemide

1980 ◽  
Vol 27 (6) ◽  
pp. 784-790 ◽  
Author(s):  
Bo Odlind ◽  
Björn Beermann
Keyword(s):  
Tubular Secretion ◽  
Renal Tubular Secretion ◽  
Renal Tubular
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