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Pharmaceutical Research

, Volume 24, Issue 1, pp 48–57 | Cite as

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

  • Pakawadee Sermsappasuk
  • Osama Abdelrahman
  • Michael Weiss
Research Paper

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.

Key words

heart p-glycoprotein pharmacokinetic/pharmacodynamic model tolerance verapamil 

Abbreviations

CVR

coronary vascular resistance

LVDP

left ventricular developed pressure

Pgp

P-glycoprotein

PK/PD

pharmacokinetic/pharmacodynamic

Notes

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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Copyright information

© Springer Science + Business Media, Inc. 2006

Authors and Affiliations

  • Pakawadee Sermsappasuk
    • 1
  • Osama Abdelrahman
    • 1
  • Michael Weiss
    • 1
  1. 1.Section of Pharmacokinetics, Department of PharmacologyMartin Luther University Halle-WittenbergHalleGermany

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