scholarly journals Characterization of the Inhibitory Effects of N-Butylpyridinium Chloride and Structurally Related Ionic Liquids on Organic Cation Transporters 1/2 and Human Toxic Extrusion Transporters 1/2-K In Vitro and In Vivo

2011 ◽  
Vol 39 (9) ◽  
pp. 1755-1761 ◽  
Author(s):  
Yaofeng Cheng ◽  
Lucy J. Martinez-Guerrero ◽  
Stephen H. Wright ◽  
Robert K. Kuester ◽  
Michelle J. Hooth ◽  
...  
Keyword(s):  
Ionic Liquids ◽  
Organic Cation ◽  
Organic Cation Transporters ◽  
Inhibitory Effects ◽  
Cation Transporters

Nitric oxide-induced regulation of renal organic cation transport after renal ischemia-reperfusion injury

2011 ◽  
Vol 301 (5) ◽  
pp. F997-F1004 ◽  
Author(s):  
R. Schneider ◽  
M. Meusel ◽  
B. Betz ◽  
M. Kersten ◽  
K. Möller-Ehrlich ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Organic Cation ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Fractional Excretion ◽  
Renal Ischemia ◽  
Organic Cation Transporters ◽  
Cation Transporters

Renal organic cation transporters are downregulated by nitric oxide (NO) in rat endotoxemia. NO generated by inducible NO synthase (iNOS) is substantially increased in the renal cortex after renal ischemia-reperfusion (I/R) injury. Therefore, we investigated the effects of iNOS-specific NO inhibition on the expression of the organic cation transporters rOct1 and rOct2 (Slc22a1 and Slc22a2, respectively) after I/R injury both in vivo and in vitro. In vivo, N6-(1-iminoethyl)-l-lysine (l-NIL) completely inhibited NO generation after I/R injury. Moreover, l-NIL abolished the ischemia-induced downregulation of rOct1 and rOct2 as determined by qPCR and Western blotting. Functional evidence was obtained by measuring the fractional excretion (FE) of the endogenous organic cation serotonin. Concordant with the expression of the rate-limiting organic cation transporter, the FE of serotonin decreased after I/R injury and was totally abolished by l-NIL. In vitro, ischemia downregulated both rOct1 and rOct2, which were also abolished by l-NIL; the same was true for the uptake of the organic cation MPP. We showed that renal I/R injury downregulates rOct1 and rOct2, which is most probably mediated via NO. In principle, this may be an autocrine effect of proximal tubular epithelial cells. We conclude that rOct1, or rOct1 and rOct2 limit the rate of the renal excretion of serotonin.

scholarly journals MOXIFLOXACIN IS A POTENTIN VITROINHIBITOR OF OCT- AND MATE-MEDIATED TRANSPORT OF METFORMIN AND ETHAMBUTOL

2016 ◽  
pp. AAC.01471-16 ◽  
Author(s):  
Lindsey H. M. te Brake ◽  
Jeroen J. M. W. van den Heuvel ◽  
Aaron Ohene Buaben ◽  
Reinout van Crevel ◽  
Albert Bilos ◽  
...  
Keyword(s):  
Organic Cation ◽  
Potent Inhibitor ◽  
Drug Uptake ◽  
Hek293 Cells ◽  
Organic Cation Transporters ◽  
Interaction Study ◽  
Inhibitory Effects ◽  
Mechanistic Basis

Introduction: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 (MATEs). Thus any DDIs would primarily be mediated via these transporters. This study aimed to assess thein vitroinhibitory effects of TB drugs (rifampicin, isoniazid, pyrazinamide, ethambutol, amikacin, moxifloxacin and linezolid) on metformin transport, and whether TB drugs are also substrates themselves of OCTs and MATEs.Methods:HEK293 cells overexpressing OCT1, OCT2, OCT3, MATE1 and MATE2K were used to study TB drug-mediated inhibition of [14C]metformin uptake and to test if TB drugs are transporter substrates. Metformin uptake was determined by quantifying [14C]metformin radioactivity and TB drug uptake was analysed using LC-MS/MS. DDI-indices were calculated (plasma Cmax/IC50), and based on literature a cut-off of >0.1 was assumed to warrant furtherin vivoinvestigation.Results:Moxifloxacin was the only TB drug identified as a potent inhibitor (DDI-index>0.1) of MATE1- and MATE2K-mediated metformin transport (IC50of 12 μM (95% CI 5.1-29 μM) and 7.6 μM (95% CI 0.2-242 μM), respectively). Of all TB drugs, only ethambutol appeared to be a substrate of OCT1, OCT2, OCT3, MATE1 and MATE2K. MATE1-mediated ethambutol uptake was inhibited strongly (DDI-index >0.1) by moxifloxacin (IC5012 μM (95% CI 3.4-43 μM)).Conclusions:Our findings provide a mechanistic basis for DDI-predictions concerning ethambutol. According to international guidelines, anin vivointeraction study is warranted for the observedin vitrointeraction between ethambutol and moxifloxacin.

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.

Cloning and Characterization of Two Human Polyspecific Organic Cation Transporters

1997 ◽  
Vol 16 (7) ◽  
pp. 871-881 ◽  
Author(s):  
VALENTIN GORBOULEV ◽  
JOCHEN C. ULZHEIMER ◽  
AIDA AKHOUNDOVA ◽  
ISABEL ULZHEIMER-TEUBER ◽  
ULRICH KARBACH ◽  
...  
Keyword(s):  
Organic Cation ◽  
Organic Cation Transporters ◽  
Cation Transporters

Differential pharmacological in vitro properties of organic cation transporters and regional distribution in rat brain

2006 ◽  
Vol 50 (8) ◽  
pp. 941-952 ◽  
Author(s):  
Anne Amphoux ◽  
Vincent Vialou ◽  
Eva Drescher ◽  
Michael Brüss ◽  
Clotilde Mannoury La Cour ◽  
...  
Keyword(s):  
Rat Brain ◽  
Organic Cation ◽  
Regional Distribution ◽  
Organic Cation Transporters ◽  
Cation Transporters

Multiple binding sites in organic cation transporters require sophisticated procedures to identify interactions of novel drugs

2019 ◽  
Vol 400 (2) ◽  
pp. 195-207 ◽  
Author(s):  
Hermann Koepsell
Keyword(s):  
Binding Sites ◽  
Organic Cation ◽  
Cation Binding ◽  
Organic Cation Transporters ◽  
High Affinity ◽  
Multiple Binding Sites ◽  
Novel Drugs ◽  
Cation Transporters ◽  
Influence Of Substrate

AbstractIn vitroevaluation of drugs for interaction with transporters is essential during drug development. As polyspecific organic cation transporters (OCTs) are critical for pharmacokinetics of many cationic drugs,in vitrotesting of human OCT1 and human OCT2 is recommended. In the currently applied tests it is determined whether uptake of one model cation in stably transfected epithelial cells is inhibited using a substrate concentration in the micromolar range. In this review experimental evidence for the existence of low- and high-affinity cation binding sites in OCTs that may interact with drugs is compiled. Most data were obtained from studies performed with rat Oct1. Whereas overlapping low-affinity cation binding sites are directly involved in transport, the high-affinity cation binding sites may induce allosteric inhibition of transport. Remarkably, high-affinity inhibition is only observed when uptake is measured using nanomolar substrate concentrations far below the respectiveKmvalues. Affinities of inhibitors are dependent on molecular structure and concentration of the employed substrate. Because the currently appliedin vitrotests for identification of interaction of novel drugs with OCTs do not consider the influence of substrate structure and are not capable of identifying high-affinity inhibition, more sophisticated testing protocols are proposed.

Sign in / Sign up

Export Citation Format

Share Document