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Modeling Cardiac Uptake and Negative Inotropic Response of Verapamil in Rat Heart: Effect of Amiodarone

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Abstract

Purpose

To determine the effect of the P-glycoprotein (Pgp) modulator amiodarone on the pharmacokinetics and pharmacodynamics (PK/PD) of Pgp substrate verapamil in the perfused rat heart.

Methods

In Langendorff-perfused rat hearts, the outflow concentration–time curve and inotropic response data were measured after a 1.5 nmol dose of [3H]-verapamil (infused within 1 min) in the absence and presence of the amiodarone (1 μM) in perfusate, as well as using a double dosing regimen (0.75 nmol in a 10 min interval). These data were analyzed by a PK/PD model.

Results

Amiodarone failed to influence the rapid uptake and equilibrium partitioning of verapamil into the heart. The time course of the negative inotropic effect of verapamil, including the ‘rebound’ above the original baseline after the infusion of verapamil was stopped, could be described by a PK/PD tolerance model. Tolerance development (mean delay time, 12 min) led to a reduction in predicted steady-state effect (16%). The EC50 and E max values as estimated in single dose experiments were 16.4 ± 4.1 nM and 50.5 ± 18.9 mmHg, respectively.

Conclusions

The result does not support the hypothesis that Pgp inhibition by amiodarone increases cardiac uptake of the Pgp substrate verapamil.

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Abbreviations

CVR:

coronary vascular resistance

LVDP:

left ventricular developed pressure

Pgp:

P-glycoprotein

PK/PD:

pharmacokinetic/pharmacodynamic

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Acknowledgments

We thank the reviewers for insightful comments. Pakawadee Sermsappasuk is supported by a Royal Thai Government scholarship under the Committee Staff Development Project of Commission on Higher Education.

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Authors and Affiliations

  1. Section of Pharmacokinetics, Department of Pharmacology, Martin Luther University Halle-Wittenberg, D-06097, Halle, Germany

    Pakawadee Sermsappasuk, Osama Abdelrahman & Michael Weiss

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  1. Pakawadee Sermsappasuk
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  2. Osama Abdelrahman
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Correspondence to Michael Weiss.

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Sermsappasuk, P., Abdelrahman, O. & Weiss, M. Modeling Cardiac Uptake and Negative Inotropic Response of Verapamil in Rat Heart: Effect of Amiodarone. Pharm Res 24, 48–57 (2007). https://doi.org/10.1007/s11095-006-9117-z

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  • DOI: https://doi.org/10.1007/s11095-006-9117-z

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