The Mechanism of the Renal Excretion of Disopyramide in Rats. I

Itô, Tatsuya; Tomidokoro, Kenkichi; Nishino, T.; Fukuzawa, Yuichi; Chiba, Kazumoto; Miyazaki, Shôzo

doi:10.1248/yakushi1947.112.5_336

Cited by 4 publications

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“…After the administration of DP, 26.2 ( 2.1% of the dose was excreted as unchanged drug, while 4.1 ( 0.9% was excreted as MND in the urine within 24 h. Table 2 lists the pharmacokinetic parameters, which are in agreement with the published data. 15,16 EM did not significantly change the pharmacokinetic parameters of DP, and both the plasma concentrations and the urinary excretion of the metabolite, MND, were not also significantly changed. Moreover, the plasma free fraction of DP (f p ), 0.800-0.875, was almost constant over the concentration range of 0.05-15.0 µg/mL and was not significantly changed in the presence of EM.…”

Section: Resultsmentioning

confidence: 81%

“…Effects of EM on Pharmacokinetics of DPsThe pharmacokinetic parameters of DP obtained here were is close agreement with those noted in previous studies. 15,16 Since the total plasma clearance of DP was large and thought to be blood flow-limited, we evaluated the effects of EM on the pharmacokinetics of DP following portal vein administration of DP.…”

Section: Discussionmentioning

confidence: 99%

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Pharmacodynamic analysis of the electrocardiographic interaction between disopyramide and erythromycin in rats

Hanada

Ohtani

Kotaki

et al. 1999

Journal of Pharmaceutical Sciences

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Disopyramide (DP) is known to induce QT prolongation and Torsades de Pointes (TdP) when administered concomitantly with erythromycin (EM). To define and evaluate quantitatively the arrhythmogenic risk of the concomitant administration of DP and EM, we investigated the influence of EM on the pharmacokinetics and pharmacodynamics of DP in rats. The time profiles of change in QT interval and plasma concentration of each drug were evaluated during and after constant intravenous infusion of DP (6.0 or 15.0 mg/kg/h), EM (4.0 or 8.0 mg/kg/h), and coadministration of DP and EM (DP 6.0 mg/kg/h plus EM 4.0 mg/kg/h). Each agent induced QT prolongation at plasma concentrations within the therapeutic range in humans. DP-induced QT prolongation was proportional to its plasma concentration. In the case of EM, the Emax model with an "effect compartment" could explain the relationship between plasma EM concentrations and changes in QT interval. Although coadministration of EM with DP gave enhanced QT prolongation compared to dosing with DP alone, EM did not affect the pharmacokinetics of DP. In conclusion, it was shown that a pharmacodynamic interaction contributes to the electrocardiographic adverse reaction (i.e., QT prolongation) induced by coadministration of DP and EM in rats.

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Section: Resultsmentioning

confidence: 81%

Section: Discussionmentioning

confidence: 99%

Pharmacodynamic analysis of the electrocardiographic interaction between disopyramide and erythromycin in rats

Hanada

Ohtani

Kotaki

et al. 1999

Journal of Pharmaceutical Sciences

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Renal Drug Transporters and Drug Interactions

et al. 2017

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Transporters in proximal renal tubules contribute to the disposition of numerous drugs. Furthermore, the molecular mechanisms of tubular secretion have been progressively elucidated during the past decades. Organic anions tend to be secreted by the transport proteins OAT1, OAT3 and OATP4C1 on the basolateral side of tubular cells, and multidrug resistance protein (MRP) 2, MRP4, OATP1A2 and breast cancer resistance protein (BCRP) on the apical side. Organic cations are secreted by organic cation transporter (OCT) 2 on the basolateral side, and multidrug and toxic compound extrusion (MATE) proteins MATE1, MATE2/2-K, P-glycoprotein, organic cation and carnitine transporter (OCTN) 1 and OCTN2 on the apical side. Significant drug-drug interactions (DDIs) may affect any of these transporters, altering the clearance and, consequently, the efficacy and/or toxicity of substrate drugs. Interactions at the level of basolateral transporters typically decrease the clearance of the victim drug, causing higher systemic exposure. Interactions at the apical level can also lower drug clearance, but may be associated with higher renal toxicity, due to intracellular accumulation. Whereas the importance of glomerular filtration in drug disposition is largely appreciated among clinicians, DDIs involving renal transporters are less well recognized. This review summarizes current knowledge on the roles, quantitative importance and clinical relevance of these transporters in drug therapy. It proposes an approach based on substrate-inhibitor associations for predicting potential tubular-based DDIs and preventing their adverse consequences. We provide a comprehensive list of known drug interactions with renally-expressed transporters. While many of these interactions have limited clinical consequences, some involving high-risk drugs (e.g. methotrexate) definitely deserve the attention of prescribers.

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The Transport Mechanism of an Organic Cation, Disopyramide, by Brush-border Membranes. Comparison Between Renal Cortex and Small Intestine of the Rat

Itoh

Kobayashi

Sugawara

et al. 1993

Journal of Pharmacy and Pharmacology

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The characteristics of disopyramide uptake in brush-border membrane vesicles isolated from rat renal cortex and small intestine were investigated. Transport of disopyramide into an osmotically reactive intravesicular space was observed with notable binding to the membrane surface. An outwardly directed H+ gradient stimulated disopyramide uptake, resulting in a transient uphill transport in both brush-border membranes. As for the renal brush-border membrane, the H+ gradient itself appeared to be the driving force for this stimulation of uptake. These findings suggest that disopyramide-H+ antiport is the mechanism of disopyramide action in renal cell membrane. The initial uptake was saturable (Km and Vmax of 68.0 microM and 1.25 nmol (mg protein)-1/30 s, respectively). The stimulation of disopyramide uptake by an outward H+ gradient in rat intestinal brush-border membrane was due to an interior negative H(+)-diffusion potential. A K(+)-diffusion potential (interior negative) enhanced disopyramide uptake. These results suggest that there are different mechanisms of disopyramide uptake for renal and intestinal brush-border membrane vesicles.

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The Mechanism of the Renal Excretion of Disopyramide in Rats. I

Cited by 4 publications

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Pharmacodynamic analysis of the electrocardiographic interaction between disopyramide and erythromycin in rats

Pharmacodynamic analysis of the electrocardiographic interaction between disopyramide and erythromycin in rats

Renal Drug Transporters and Drug Interactions

The Transport Mechanism of an Organic Cation, Disopyramide, by Brush-border Membranes. Comparison Between Renal Cortex and Small Intestine of the Rat

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