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Vol. 300, Issue 2, 688-694, February 2002

P-Glycoprotein Inhibitors Enhance Saturable Uptake of Idarubicin in Rat Heart: Pharmacokinetic/Pharmacodynamic Modeling

Michael Weiss and Wonku Kang

Section of Pharmacokinetics, Department of Pharmacology, Martin Luther University Halle-Wittenberg, Halle, Germany

Little is known about cardiac uptake kinetics of idarubicin, including a possible protective role of P-glycoprotein (Pgp)-mediated transport. This study therefore investigated uptake and negative inotropic action of idarubicin in the single-pass isolated perfused rat heart by using a pharmacokinetic/pharmacodynamic modeling approach. Idarubicin was administered as a 10-min constant infusion of 0.5 mg followed by a 70-min washout period in the absence and presence of the Pgp antagonists verapamil or amiodarone. Outflow concentration and left ventricular developed pressure were measured and the model parameters were estimated by simultaneous nonlinear regression. The results indicate the existence of a saturable, Michaelis-Menten type uptake process into the heart (Km = 3.06 µM, Vmax = 46.0 µM/min). Verapamil and amiodarone significantly enhanced the influx rate (Vmax increased 1.8-fold), suggesting that idarubicin is transported by Pgp directly out of the membrane before it gets into the cell. Verapamil and amiodarone attenuated the negative inotropic action of idarubicin, which was linked to the intracellular concentration of idarubicin.

0022-3565/02/3002-0688$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2002 by The American Society for Pharmacology and Experimental Therapeutics


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Copyright © 2002 by the American Society for Pharmacology and Experimental Therapeutics.