Competitive inhibition of renal tubular secretion of ciprofloxacin and metabolite by probenecid

ABSTRACT Probenecid interacts with transport processes of drugs at several sites in the body. For most quinolones, renal clearance is reduced by concomitant administration of probenecid. The interaction between gemifloxacin and probenecid has not yet been studied. We studied the extent, time course, site(s), and mechanism of this interaction. Seventeen healthy volunteers participated in a randomized, two-way crossover study. Subjects received 320 mg gemifloxacin as an oral tablet without and with 4.5 g probenecid divided in eight oral doses. Drug concentrations in plasma and urine were analyzed by liquid chromatography-tandem mass spectrometry. WinNonlin was used for noncompartmental analysis, compartmental modeling, and statistics, and NONMEM was used for visual predictive checks. Concomitant administration of probenecid increased plasma gemifloxacin concentrations and amounts excreted in urine compared to baseline amounts. Data are average estimates (percent coefficients of variation). Modeling showed a competitive inhibition of the renal tubular secretion of gemifloxacin by probenecid as the most likely mechanism of the interaction. The estimated Km and V max for the saturable part of renal elimination were 9.16 mg/liter (20%) and 113 mg/h (21%), respectively. Based on the molar ratio, the affinity for the renal transporter was 10-fold higher for gemifloxacin than for probenecid. Since probenecid reached an ∼200-times-higher area under the molar concentration-time curve from 0 to 24 h than gemifloxacin, probenecid inhibited the active tubular secretion of gemifloxacin. Probenecid also reduced the nonrenal clearance of gemifloxacin from 25.2 (26%) to 21.0 (23%) liters/h. Probenecid inhibited the renal tubular secretion of gemifloxacin, most likely by a competitive mechanism, and slightly decreased nonrenal clearance of gemifloxacin.

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Inhibition kinetics of cationic drugs on N′-methylnicotinamide uptake by brush border membrane vesicles from the dog kidney cortex

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y90-066 ◽

1990 ◽

Vol 68 (4) ◽

pp. 467-475 ◽

Cited By ~ 10

Author(s):

Reina Bendayan ◽

Edward M. Sellers ◽

Melvin Silverman

Keyword(s):

Transport System ◽

Competitive Inhibition ◽

Membrane Vesicles ◽

Tubular Secretion ◽

Kidney Cortex ◽

Organic Base ◽

Renal Tubular Secretion ◽

Cationic Drugs ◽

Dog Kidney ◽

Renal Tubular

The effect of cationic drugs on the uptake of the prototypical organic cation N′-methylnicotinamide has been evaluated. Using purified brash border membrane vesicles prepared from dog kidney cortex and applying a rapid Millipore filtration technique, cationic drugs apparent inhibitory constants (Ki) were calculated from kinetic analysis of N′-methylnicotinamide uptake corrected for noncarrier-mediated transport (10 s uptake; outwardly directed H+ gradient; pH 7.4, 25 °C). All of the cationic drugs tested exhibited competitive inhibition of N′-methylnicotinamide uptake suggesting that they all share the organic base transport system at the renal proximal tubule. The Ki values were as follows, in order of decreasing apparent affinity: quinidine (0.7 μM), trimethoprim (1.3 μM), cimetidine (2.0 μM), famotidine (3.0 μM), quinine (7.0 μM), amiloride (5.8 μM), procainamide (21 μM), and nizatidine (30 μM). The different relative affinities of the drugs for the organic base transport system may explain the mutual competition for renal tubular secretion observed when cationic drugs are administered concurrently in vivo, e.g., trimethoprim–procainamide and cimetidine–procainamide. The approach outlined in the present study should prove useful to predict complex drug interactions in clinical pharmacology.Key words: renal tubular secretion, membrane transport, cationic drugs, N′-methylnicotinamide.

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Abstract 14035: Renal Tubular Secretion and Cardiac Distribution of Dofetilide is Dependent on MATE1 Function

Circulation ◽

10.1161/circ.142.suppl_3.14035 ◽

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.

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