The Effect of Lactate on Sex Differences in Rat Renal Tubular Energy-Dependent Transport of the Organic Cation Amantadine

Pharmacology ◽  
2001 ◽  
Vol 62 (3) ◽  
pp. 188-192 ◽  
Author(s):  
Bradley Bobby ◽  
Daniel S. Sitar
Keyword(s):  
Sex Differences ◽  
Organic Cation ◽  
Renal Tubular ◽  
Dependent Transport ◽  
Energy Dependent

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.

Energy dependent transport length scales in strongly diffusive carbon nanotubes

2006 ◽  
Vol 18 (19) ◽  
pp. 4581-4587 ◽  
Author(s):  
B Lassagne ◽  
B Raquet ◽  
J M Broto ◽  
J González
Keyword(s):  
Carbon Nanotubes ◽  
Length Scales ◽  
Transport Length ◽  
Dependent Transport ◽  
Energy Dependent

ATP-dependent transport of tetraethylammonium by endosomes isolated from rat renal cortex

1994 ◽  
Vol 266 (6) ◽  
pp. F966-F976 ◽  
Author(s):  
J. B. Pritchard ◽  
D. B. Sykes ◽  
R. Walden ◽  
D. S. Miller
Keyword(s):  
Organic Cation ◽  
Renal Cortex ◽  
Ph Gradient ◽  
Organic Cations ◽  
Tubular Cells ◽  
Active Space ◽  
Intracellular Organelles ◽  
Dependent Transport ◽  
Endosomal Vesicles ◽  
Dependent Mechanism

During renal organic cation secretion by some species, intracellular concentrations greatly exceed the 10- to 15-fold ratio predicted by the potential-driven mechanism thought to mediate their basolateral uptake. Free cytoplasmic organic cation concentrations within the tubular cells might be decreased through sequestration within intracellular organelles. The data reported here show that endosomal vesicles isolated from rat renal cortex take up tetraethylammonium (TEA) by an ATP-dependent mechanism. Addition of 0.2-5 mM ATP to the medium stimulated uptake 5- to 10-fold at 5 min and 20-fold at 60 min. More than 80% of the ATP-dependent uptake was associated with an osmotically active space. The nonhydrolyzable ATP analogue, adenosine 5'-O-(3-thiotriphosphate), did not stimulate TEA uptake. Mg2+ and Cl- were required for stimulation. Uptake was inhibited by several organic cations, including TEA itself. Uptake was also inhibited by inhibitors of intravesicular acidification, e.g., monensin and N-ethylmaleimide. Furthermore, the ATP requirement could be bypassed by establishing a pH gradient (inside acidic). These data show that endosomal TEA accumulation is mediated by proton/TEA exchange and is driven by the pH gradient maintained by H(+)-adenosinetriphosphatase. This potent sequestration mechanism may play an important role in organic cation secretion.

scholarly journals Fluoroquinolone Transport by Human Monocytes: Characterization and Comparison to Other Cells of Myeloid Lineage

2000 ◽  
Vol 44 (10) ◽  
pp. 2609-2614 ◽  
Author(s):  
Steven J. Bounds ◽  
Robin Nakkula ◽  
John D. Walters
Keyword(s):  
Inhibitory Effect ◽  
Human Monocytes ◽  
Monocytic Differentiation ◽  
Granulocytic Differentiation ◽  
Temperature Dependent ◽  
Myeloid Lineage ◽  
Transport Pathways ◽  
Dependent Transport ◽  
Energy Dependent ◽  
Human Polymorphonuclear Leukocytes

ABSTRACT Human monocytes transport and accumulate ciprofloxacin and other fluoroquinolones. Although little is known about the mechanisms of transport, we expected monocytes to be similar to other cells of myeloid lineage. In the present study, monocyte fluoroquinolone transport was characterized and compared to the corresponding transport pathways of human polymorphonuclear leukocytes (PMNs) and HL-60 cells. Ciprofloxacin transport by monocytes was saturable, temperature dependent, sodium independent, and relatively insensitive to pH. Quiescent monocytes transported ciprofloxacin with aKm of 171 μg/ml and aV max of 32.7 ng/min/106 cells. Adenine competitively inhibited ciprofloxacin transport by quiescent monocytes (Ki = 3.8 mM), but nucleosides had no significant inhibitory effect. In all of these respects, transport by monocytes was similar to that observed for quiescent PMNs and immature HL-60 cells. Unlike PMNs, however, monocytes and immature HL-60 cells did not exhibit dramatically enhanced ciprofloxacin transport when activated by phorbol myristate acetate (PMA). Consistent with this finding, HL-60 cells committed to granulocytic differentiation exhibited a significant component of PMA-inducible ciprofloxacin transport activity, while HL-60 cells committed to monocytic differentiation did not. In PMNs, the PMA-inducible component of transport appeared to be mobilized from a granule compartment, since its activity could be modulated by agents that enhance or inhibit stimulated degranulation. Thus, quiescent monocytes, PMNs, and HL-60 cells take up ciprofloxacin via similar energy-dependent transport mechanisms. Unlike granulocytes, monocytes do not express a second, higher-affinity pathway for ciprofloxacin accumulation when they are activated by PMA.

On the Energy-Dependent Transport Equation

1963 ◽  
Vol 15 (4) ◽  
pp. 476-477 ◽  
Author(s):  
G. C. Summerfield ◽  
P. F. Zweifel
Keyword(s):  
Transport Equation ◽  
Dependent Transport ◽  
Energy Dependent

Citrate transport in Salmonella typhimurium: studies with 2-fluoro-L-erythro-citrate as a substrate

1980 ◽  
Vol 58 (10) ◽  
pp. 797-803 ◽  
Author(s):  
D. M. Ashton ◽  
G. D. Sweet ◽  
J. M. Somers ◽  
W. W. Kay
Keyword(s):  
Salmonella Typhimurium ◽  
Transport System ◽  
Protein C ◽  
Competitive Inhibitor ◽  
C Protein ◽  
High Affinity ◽  
Citrate Transport ◽  
Resistant Mutants ◽  
Dependent Transport ◽  
Energy Dependent

The citrate analogue, 2-fluoro-L-erythro-[3,4,5,6-14C]citrate was synthesized as a probe for the citrate transport system of Salmonella typhimurium. This analogue was actively transported by an inducible energy-dependent transport system with high affinity for fluorocitrate (Km = 3.3 μM), and this transport system was inhibited competitively by citrate and isocitrate. Fluorocitrate was shown to be a competitive inhibitor of the citrate-binding protein (C protein) of this organism (Ki = 4–5 μM). Analogue resistant mutants were simultaneously defective in fluorocitrate transport as well as the C protein and the affected allele, tctC, was located at 59 units on the S. typhimurium chromosome map. These tctC mutants were shown to be specifically defective in K+-dependent fluorocitrate transport but still retained another system capable of transporting fluorocitrate in the presence of both Na+ and K+.

Energy Dependent Transport of Xenobiotics and Its Relevance to Multidrug Resistance

2003 ◽  
Vol 3 (2) ◽  
pp. 89-107 ◽  
Author(s):  
Rajendra Sharma ◽  
Yogesh Awasthi ◽  
Yusong Yang ◽  
Abha Sharma ◽  
Sharad Singhal ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Dependent Transport ◽  
Energy Dependent
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