Disopyramide concentrations in human plasma and saliva: Comparison of disopyramide concentrations in saliva and plasma unbound concentrations

Sagawa, Kenichi; Mohri, Kiminori; Shimada, Satoshi; Shimizu, Masanao; Muramatsu, Jun

doi:10.1007/s002280050250

Cited by 7 publications

(6 citation statements)

References 22 publications

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“…However, actual bioavailability in vivo is less than this due to pharmacokinetic factors such as plasma protein binding. 1 and 2 μM of disopyramide and quinidine likely constitute realistic maximal unbound concentrations (Sagawa et al, 1997 ). To encompass likely total as well as unbound concentrations, we elected to simulate effects of a wide range of concentrations of both agents (0.2–20 μM) at the single cell level, and a narrower set of more “clinically-relevant” concentrations (1, 2, 5, 10 μM) at the tissue level (represented by light blue shaded regions on dose-response curves in Figures 1 , 2 ).…”

Section: Methodsmentioning

confidence: 99%

Computational Analysis of the Mode of Action of Disopyramide and Quinidine on hERG-Linked Short QT Syndrome in Human Ventricles

Whittaker

Benson

et al. 2017

Front. Physiol.

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The short QT syndrome (SQTS) is a rare cardiac disorder associated with arrhythmias and sudden death. Gain-of-function mutations to potassium channels mediating the rapid delayed rectifier current, IKr, underlie SQTS variant 1 (SQT1), in which treatment with Na+ and K+ channel blocking class Ia anti-arrhythmic agents has demonstrated some efficacy. This study used computational modeling to gain mechanistic insights into the actions of two such drugs, disopyramide and quinidine, in the setting of SQT1. The O'Hara-Rudy (ORd) human ventricle model was modified to incorporate a Markov chain formulation of IKr describing wild type (WT) and SQT1 mutant conditions. Effects of multi-channel block by disopyramide and quinidine, including binding kinetics and altered potency of IKr/hERG channel block in SQT1 and state-dependent block of sodium channels, were simulated on action potential and multicellular tissue models. A one-dimensional (1D) transmural ventricular strand model was used to assess prolongation of the QT interval, effective refractory period (ERP), and re-entry wavelength (WL) by both drugs. Dynamics of re-entrant excitation waves were investigated using a 3D human left ventricular wedge model. In the setting of SQT1, disopyramide, and quinidine both produced a dose-dependent prolongation in (i) the QT interval, which was primarily due to IKr block, and (ii) the ERP, which was mediated by a synergistic combination of IKr and INa block. Over the same range of concentrations quinidine was more effective in restoring the QT interval, due to more potent block of IKr. Both drugs demonstrated an anti-arrhythmic increase in the WL of re-entrant circuits. In the 3D wedge, disopyramide and quinidine at clinically-relevant concentrations decreased the dominant frequency of re-entrant excitations and exhibited anti-fibrillatory effects; preventing formation of multiple, chaotic wavelets which developed in SQT1, and could terminate arrhythmias. This computational modeling study provides novel insights into the clinical efficacy of disopyramide and quinidine in the setting of SQT1; it also dissects ionic mechanisms underlying QT and ERP prolongation. Our findings show that both drugs demonstrate efficacy in reversing the SQT1 phenotype, and indicate that disopyramide warrants further investigation as an alternative to quinidine in the treatment of SQT1.

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Section: Methodsmentioning

confidence: 99%

Computational Analysis of the Mode of Action of Disopyramide and Quinidine on hERG-Linked Short QT Syndrome in Human Ventricles

Whittaker

Benson

et al. 2017

Front. Physiol.

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“…The class I AADs investigated here included disopyramide, quinidine, and propafenone. Taking into account plasma protein binding, estimates of the most likely unbound concentrations of propafenone, disopyramide, and quinidine have been given as~0.15-1 µM [85][86][87], 1 µM, and 2 µM [88], respectively. To encompass the likely total as well as unbound concentrations, we chose to simulate the effects of a wide range of concentrations of propafenone (low dose Prop_L: 0.2, medium dose Prop_M: 0.5, and high dose Prop_H: 0.8 µM), disopyramide (Diso_L: 1.0, Diso_M: 2.0, and Diso_H: 5.0 µM), and quinidine (Quin_L: 1.0, Quin_M: 2.0, and Quin_H: 5.0 µM) [37,89].…”

Section: Antiarrhythmic Effects Of Class I Drugs On Dvdt Max and Apd mentioning

confidence: 99%

In Silico Assessment of Class I Antiarrhythmic Drug Effects on Pitx2-Induced Atrial Fibrillation: Insights from Populations of Electrophysiological Models of Human Atrial Cells and Tissues

Bai

Zhu

et al. 2021

IJMS

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Electrical remodelling as a result of homeodomain transcription factor 2 (Pitx2)-dependent gene regulation was linked to atrial fibrillation (AF) and AF patients with single nucleotide polymorphisms at chromosome 4q25 responded favorably to class I antiarrhythmic drugs (AADs). The possible reasons behind this remain elusive. The purpose of this study was to assess the efficacy of the AADs disopyramide, quinidine, and propafenone on human atrial arrhythmias mediated by Pitx2-induced remodelling, from a single cell to the tissue level, using drug binding models with multi-channel pharmacology. Experimentally calibrated populations of human atrial action po-tential (AP) models in both sinus rhythm (SR) and Pitx2-induced AF conditions were constructed by using two distinct models to represent morphological subtypes of AP. Multi-channel pharmaco-logical effects of disopyramide, quinidine, and propafenone on ionic currents were considered. Simulated results showed that Pitx2-induced remodelling increased maximum upstroke velocity (dVdtmax), and decreased AP duration (APD), conduction velocity (CV), and wavelength (WL). At the concentrations tested in this study, these AADs decreased dVdtmax and CV and prolonged APD in the setting of Pitx2-induced AF. Our findings of alterations in WL indicated that disopyramide may be more effective against Pitx2-induced AF than propafenone and quinidine by prolonging WL.

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“…Class I AADs investigated here included disopyramide, quinidine and propafenone. Taking into account plasma protein binding, estimates of the most likely unbound concentrations of propafenone, disopyramide and quinidine have been given as ~0.15-1 μM [83][84][85], 1 μM and 2 μM [86], respectively. To encompass likely total as well as unbound concentrations, we selected to simulate effects of a wide range of concentration of propafenone (low dose Prop_L: 0.2, medium dose Prop_M: 0.5 and high dose Prop_H: 0.8 μM), disopyramide (Diso_L: 1.0, Diso_M: 2.0 and Diso_H: 5.0 μM) and quinidine (Quin_L: 1.0, Quin_M: 2.0 and Quin_H: 5.0 μM) [37,87].…”

Section: Antiarrhythmic Effects Of Class I Drugs On Dvdtmax and Apd90mentioning

confidence: 99%

In Silico Assessment of Class I Antiarrhythmic Drugs Effects on Pitx2-induced Atrial Fibrillation: Insights from Populations of Electrophysiological Models of Human Atrial Cells and Tissues

Bai¹,

Zhu²,

Lo³

et al. 2020

Preprint

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Electrical remodelling as a result of the homeodomain transcription factor 2 (Pitx2)‐dependent gene regulation was linked to atrial fibrillation (AF) and AF patients with single nucleotide polymorphisms at chromosome 4q25 responded favorably to Class I antiarrhythmic drugs (AADs). The possible reasons behind this remain elusive. The purpose of this study was to assess the efficacy of AADs disopyramide, quinidine, and propafenone on human atrial arrhythmias mediated by Pitx2-induced remodelling, from a single cell to the tissue level, using drug binding models with multi-channel pharmacology. Experimentally calibrated populations of human atrial action potential (AP) models in both sinus rhythm (SR) and Pitx2-induced AF conditions were constructed by using two distinct models to represent morphological subtypes of AP. Multi-channel pharmacological effects of disopyramide, quinidine, and propafenone on ionic currents were considered. Simulated results showed that Pitx2-induced remodelling increased maximum upstroke velocity (dVdtmax) and conduction velocity (CV), and decreased AP duration (APD) and wavelength (WL). At the concentrations tested in this study, these AADs decreased dVdtmax and CV and prolonged APD in the setting of Pitx2-induced AF. Our findings of alterations in WL indicated that quinidine and disopyramide may be more effective against Pitx2-induced AF than propafenone by prolonging WL.

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Disopyramide concentrations in human plasma and saliva: Comparison of disopyramide concentrations in saliva and plasma unbound concentrations

Abstract: Disopyramide concentrations in saliva correlated well with plasma unbound concentrations on the elimination phase.

Cited by 7 publications

References 22 publications

Computational Analysis of the Mode of Action of Disopyramide and Quinidine on hERG-Linked Short QT Syndrome in Human Ventricles

Computational Analysis of the Mode of Action of Disopyramide and Quinidine on hERG-Linked Short QT Syndrome in Human Ventricles

In Silico Assessment of Class I Antiarrhythmic Drug Effects on Pitx2-Induced Atrial Fibrillation: Insights from Populations of Electrophysiological Models of Human Atrial Cells and Tissues

In Silico Assessment of Class I Antiarrhythmic Drugs Effects on Pitx2-induced Atrial Fibrillation: Insights from Populations of Electrophysiological Models of Human Atrial Cells and Tissues

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