Evaluation of the potential interaction between tofacitinib and drugs that undergo renal tubular secretion using metformin, an in vivo marker of renal organic cation transporter 2

2014 ◽  
Vol 3 (6) ◽  
pp. 499-507 ◽  
Author(s):  
Karen J. Klamerus ◽  
Christine Alvey ◽  
Lei Li ◽  
Bo Feng ◽  
Rong Wang ◽  
...  
Keyword(s):  
Organic Cation ◽  
Organic Cation Transporter ◽  
Tubular Secretion ◽  
Potential Interaction ◽  
Renal Tubular Secretion ◽  
Organic Cation Transporter 2 ◽  
Renal Tubular

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.

scholarly journals Renal secretion of hydrochlorothiazide involves organic anion transporter 1/3, organic cation transporter 2, and multidrug and toxin extrusion protein 2-K

2019 ◽  
Vol 317 (4) ◽  
pp. F805-F814
Author(s):  
Jia Yin ◽  
David J. Wagner ◽  
Bhagwat Prasad ◽  
Nina Isoherranen ◽  
Kenneth E. Thummel ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Organic Cation ◽  
Organic Anion ◽  
Organic Cation Transporter ◽  
Tubular Secretion ◽  
Organic Anion Transporter ◽  
Anion Transporters ◽  
Anion Transporter ◽  
Organic Cation Transporter 2 ◽  
Toxin Extrusion

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.

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]

scholarly journals The Role of NF-kB in the Downregulation of Organic Cation Transporter 2 Expression and Renal Cation Secretion in Kidney Disease

2022 ◽  
Vol 8 ◽  
Author(s):  
Chao Han ◽  
Juan Zheng ◽  
Fengyi Wang ◽  
Qingyang Lu ◽  
Qingfa Chen ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Organic Cation ◽  
Rat Kidney ◽  
Basolateral Membrane ◽  
Kidney Injury ◽  
Organic Cation Transporter ◽  
Tubular Secretion ◽  
Gene Reporter Assay ◽  
Organic Cation Transporter 2

Organic cation transporter 2 (OCT2), encoded by the SLC22A2 gene, is the main cation transporter on the basolateral membrane of proximal tubular cells. OCT2 facilitates the entry step of the vectorial transport of most cations from the peritubular space into the urine. OCT2 downregulation in kidney disease models is apparent, yet not clear from a mechanistic vantage point. The aim of this study was to explore the role of inflammation, a common thread in kidney disease, and NF-kB in OCT2 modulation and tubular secretion. Among the OCTs, OCT2 was found consistently downregulated in the kidney of rats with chronic kidney disease (CKD) or acute kidney injury (AKI) and in patients diagnosed with CKD, and it was associated with the upregulation of TNFα renal expression. Exposure to TNFα reduced the expression and function of OCT2 in primary renal proximal tubule epithelial cells (RPTEC). Silencing or pharmacological inhibition of NF-kB rescued the expression of OCT2 in the presence of TNFα, indicating that OCT2 repression was NF-kB-dependent. In silico prediction coupled to gene reporter assay demonstrated the presence of at least one functional NF-kB cis-element upstream the transcription starting site of the SLC22A2 gene. Acute inflammation triggered by lipopolysaccharide injection induced TNFα expression and the downregulation of OCT2 in rat kidney. The inflammation did reduce the active secretion of the cation Rhodamine 123, with no impairment of the glomerular filtration. In conclusion, the NF-kB pathway plays a major role in the transcriptional regulation of OCT2 and, in turn, in the overall renal secretory capacity.

scholarly journals Metformin Accumulation Correlates with Organic Cation Transporter 2 Protein Expression and Predicts Mammary Tumor Regression In Vivo

2017 ◽  
Vol 10 (3) ◽  
pp. 198-207 ◽  
Author(s):  
L. Allyson Checkley ◽  
Michael C. Rudolph ◽  
Elizabeth A. Wellberg ◽  
Erin D. Giles ◽  
Reema S. Wahdan-Alaswad ◽  
...  
Keyword(s):  
Protein Expression ◽  
Mammary Tumor ◽  
Organic Cation ◽  
Tumor Regression ◽  
Organic Cation Transporter ◽  
Organic Cation Transporter 2

scholarly journals EFFECTS OF CURCUMIN AND NANOCURCUMIN ON CISPLATIN-INDUCED NEPHROTOXICITY IN RAT: COPPER TRANSPORTER 1 AND ORGANIC CATION TRANSPORTER 2 AS DRUG TRANSPORTERS

2018 ◽  
Vol 10 (1) ◽  
pp. 172
Author(s):  
Deliana Nur Ihsani Rahmi ◽  
Melva Louisa ◽  
Vivian Soetikno
Keyword(s):  
Single Dose ◽  
Organic Cation ◽  
Rat Kidney ◽  
Kidney Tissue ◽  
Organic Cation Transporter ◽  
Copper Transporter ◽  
Renal Tubular Cells ◽  
Organic Cation Transporter 2 ◽  
Renal Tubular ◽  
Copper Transporter 1

Objective: This study aimed to investigate the efficacy of curcumin (CMN) and nanocurcumin (NC) at preventing cisplatin (CDPP)-inducednephrotoxicity.Methods: Two membrane transporters, copper transporter 1 (CTR1) and organic cation transporter 2 (OCT2), have been identified involved in activeaccumulation of CDPP into renal tubular cells. We analyzed OCT2 transcription levels in rat kidney tissue and determined whether renoprotectivemechanism of CMN involves CTR1. Rats were randomly divided into five groups: (1) Control, (2) CDPP (7 mg/kg as single dose (i.p.), (3) CDPP+CMN(7 mg/kg CDPP as a single dose, i.p.+100 mg/kg/day of CMN), (4) CDPP+50 mg NC (7 mg/kg CDPP as single dose, i.p.+50 mg/kg/day NC), and(5) CDPP+100 mg NC (7 mg/kg CDPP as single dose, i.p.+100 mg/kg/day NC). Quantitative reverse transcription-polymerase chain reaction wasperformed to calculate relative expression of CTR1 and OCT2 genes in rat kidney.Results: Expression of CTR1 was unassociated with administration of CMN or NC, indicating CTR1 is uninvolved in renoprotective mechanism of CMN.The administration of 100 mg/kg/day NC increased expression of OCT2; this increase was higher compared with normal expression levels. This maybe due to another regulatory mechanism from the CMN itself.Conclusion: NC has a better renoprotective effect compared with curcumin, suggested by the increased OCT2 expression on its administration inCDPP-treated rats.

Renal tubular secretion of the alkanesulfonate 2,3-dimercapto-1-propanesulfonate

1987 ◽  
Vol 252 (5) ◽  
pp. F800-F810
Author(s):  
J. R. Stewart ◽  
G. L. Diamond
Keyword(s):  
Heavy Metals ◽  
Tubular Secretion ◽  
Selective Removal ◽  
Portal Circulation ◽  
Excretion Ratio ◽  
Renal Tubular Secretion ◽  
Removal Of Heavy Metals ◽  
Renal Tubular

The in vivo tubular secretion and metabolism of 2,3-dimercapto-1-propanesulfonate (DMPS) was examined in the chicken by use of the Sperber technique. Infusion of DMPS into the renal portal circulation of the chicken at rates equal to or less than 7.5 mumol X min-1 X kg body wt-1, resulted in a tubular excretion ratio of 0.5 for DMPS with 90% of the infused DMPS excreted in the urine unchanged. Renal tubular secretion accounted for approximately 90% of the total DMPS excreted into the urine during the infusion of DMPS at a rate of 0.75 mumol X min-1 X kg-1. The secretion of DMPS was saturable and was inhibited by p-aminohippurate (PAH), probenecid, and heptanesulfonate. Taurine (2-aminoethanesulfonate), isethionate (2-hydroxyethanesulfonate), and 2-mercaptoethanesulfonate had no effect on the secretion of DMPS or PAH. Renal tubular secretion may explain several pharmacological characteristics previously reported for DMPS, including the selective removal of heavy metals from the kidney.

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.

Renal tubular secretion of o-acetylaminohippurate

1962 ◽  
Vol 203 (5) ◽  
pp. 881-885 ◽  
Author(s):  
Gilbert H. Mudge ◽  
Keith Garlid ◽  
I. M. Weiner
Keyword(s):  
Tubular Secretion ◽  
Rabbit Kidney ◽  
Kidney Cortex ◽  
Renal Tubular Secretion ◽  
Kidney Slices ◽  
Tubular Transport ◽  
Clearance Studies ◽  
Renal Tubular Transport ◽  
Renal Tubular

Renal tubular transport of o-acetylaminohippurate (OAAH) was investigated because of previous reports that it differed from other hippurates by not undergoing tubular secretion. However, tubular secretion was readily demonstrable in nine clearance experiments in dogs. Secretion was decreased by succinate, 2,4 DNP, probenecid, hippurate, and Diodrast, substances all known to inhibit secretion of other hippurates. In vivo deacetylation was demonstrated. In slice system of rabbit kidney cortex, accumulation was also shown, but degree of uptake was complicated by deacetylation to OAH. Meta and para isomers did not undergo deacetylation. Both in clearance studies and in kidney slices, the transport of OAAH is qualitatively similar to other hippurates.

Sign in / Sign up

Export Citation Format

Share Document