Multiple organic cation transporters contribute to the renal transport of sulpiride

2017 ◽  
Vol 38 (9) ◽  
pp. 526-534 ◽  
Author(s):  
Liping Li ◽  
Yayun Weng ◽  
Wei Wang ◽  
Mengru Bai ◽  
Hongmei Lei ◽  
...  
Keyword(s):  
Organic Cation ◽  
Renal Transport ◽  
Organic Cation Transporters ◽  
Cation Transporters

Human Organic Anion Transporters and Human Organic Cation Transporters Mediate Renal Transport of Prostaglandins

2002 ◽  
Vol 301 (1) ◽  
pp. 293-298 ◽  
Author(s):  
Hiroaki Kimura ◽  
Michio Takeda ◽  
Shinichi Narikawa ◽  
Atsushi Enomoto ◽  
Kimiyoshi Ichida ◽  
...  
Keyword(s):  
Organic Cation ◽  
Organic Anion ◽  
Renal Transport ◽  
Organic Anion Transporters ◽  
Organic Cation Transporters ◽  
Anion Transporters ◽  
Cation Transporters

Transport of Dicationic Drugs Pentamidine and Furamidine by Human Organic Cation Transporters

2008 ◽  
Vol 37 (2) ◽  
pp. 424-430 ◽  
Author(s):  
Xin Ming ◽  
Wujian Ju ◽  
Huali Wu ◽  
Richard R. Tidwell ◽  
James E. Hall ◽  
...  
Keyword(s):  
Organic Cation ◽  
Organic Cation Transporters ◽  
Cation Transporters

Role of organic cation transporters in the ocular disposition of its intravenously injected substrate in rabbits: Implications for ocular drug therapy

2013 ◽  
Vol 116 ◽  
pp. 27-35 ◽  
Author(s):  
Jayabalan Nirmal ◽  
Anju Sirohiwal ◽  
Sundararajan Baskar Singh ◽  
Nihar Ranjan Biswas ◽  
Vasantha Thavaraj ◽  
...  
Keyword(s):  
Drug Therapy ◽  
Organic Cation ◽  
Organic Cation Transporters ◽  
Cation Transporters

The role of organic cation transporters (OCTs) in the transfer of metformin in the dually perfused human placenta

2010 ◽  
Vol 39 (1-3) ◽  
pp. 76-81 ◽  
Author(s):  
Kristiina Tertti ◽  
Ulla Ekblad ◽  
Tuija Heikkinen ◽  
Melissa Rahi ◽  
Tapani Rönnemaa ◽  
...  
Keyword(s):  
Human Placenta ◽  
Organic Cation ◽  
Organic Cation Transporters ◽  
Cation Transporters

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 Interaction Profiles of Central Nervous System Active Drugs at Human Organic Cation Transporters 1–3 and Human Plasma Membrane Monoamine Transporter

2021 ◽  
Vol 22 (23) ◽  
pp. 12995
Author(s):  
Thomas J. F. Angenoorth ◽  
Stevan Stankovic ◽  
Marco Niello ◽  
Marion Holy ◽  
Simon D. Brandt ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Plasma Membrane ◽  
Human Plasma ◽  
Organic Cation ◽  
Hek293 Cells ◽  
Monoamine Transporters ◽  
Organic Cation Transporters ◽  
Monoamine Transporter ◽  
Cation Transporters

Many psychoactive compounds have been shown to primarily interact with high-affinity and low-capacity solute carrier 6 (SLC6) monoamine transporters for norepinephrine (NET; norepinephrine transporter), dopamine (DAT; dopamine transporter) and serotonin (SERT; serotonin transporter). Previous studies indicate an overlap between the inhibitory capacities of substances at SLC6 and SLC22 human organic cation transporters (SLC22A1–3; hOCT1–3) and the human plasma membrane monoamine transporter (SLC29A4; hPMAT), which can be classified as high-capacity, low-affinity monoamine transporters. However, interactions between central nervous system active substances, the OCTs, and the functionally-related PMAT have largely been understudied. Herein, we report data from 17 psychoactive substances interacting with the SLC6 monoamine transporters, concerning their potential to interact with the human OCT isoforms and hPMAT by utilizing radiotracer-based in vitro uptake inhibition assays at stably expressing human embryonic kidney 293 cells (HEK293) cells. Many compounds inhibit substrate uptake by hOCT1 and hOCT2 in the low micromolar range, whereas only a few substances interact with hOCT3 and hPMAT. Interestingly, methylphenidate and ketamine selectively interact with hOCT1 or hOCT2, respectively. Additionally, 3,4-methylenedioxymethamphetamine (MDMA) is a potent inhibitor of hOCT1 and 2 and hPMAT. Enantiospecific differences of R- and S-α-pyrrolidinovalerophenone (R- and S-α-PVP) and R- and S-citalopram and the effects of aromatic substituents are explored. Our results highlight the significance of investigating drug interactions with hOCTs and hPMAT, due to their role in regulating monoamine concentrations and xenobiotic clearance.

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