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 Received August 29, 2001; accepted November 2, 2001 This paper is available online at http://jpet.aspetjournals.org ABSTRACT 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/phar- macodynamic modeling approach. Idarubicin was adminis- tered 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 (K m = 3.06 M, V max = 46.0 M/min). Verapamil and amiodarone significantly enhanced the influx rate (V max increased 1.8-fold), suggesting that idarubicin is transported by Pgp directly out of the membrane before it gets into the cell. Verapamil and ami- odarone attenuated the negative inotropic action of idarubicin, which was linked to the intracellular concentration of idarubicin. Little attention has been paid to the kinetics of drug up- take into the myocardium, despite the clinical importance of these transport mechanisms for the efficacy and toxicity of cardioactive drugs. Thus, the clinical utility of the antineo- plastic agent idarubicin is limited by a high incidence of severe and usually irreversible cardiac toxicity; however, the transport mechanism of idarubicin (and other anthracy- clines) into the heart is still unclear. Previous studies in cell lines have shown contradicting results. In multiple drug resistance (MDR) cells, membrane permeability and hydro- phobicity of anthracyclines were highly correlated (Wielinga et al., 2000), in accordance with the assumption that a highly lipophilic drug such as idarubicin would passively diffuse across the plasma membrane (Stein, 1997). However, satu- rable uptake of anthracyclines into cells also has been re- ported (Decorti et al., 1998; Sasaya et al., 1998). Further- more, anthracyclines are well known substrates for P-glycoprotein (Pgp); however, as pointed out recently, there is relatively limited information on the functional role of Pgp and related transporters in the heart (Rodriguez et al., 1999). It has been suggested that Pgp acting as a drug efflux pump can decrease the cellular concentration of some drugs and may play an important role in the protection of the heart. An increased cardiac accumulation of vinblastine (van Asperen et al., 1999a) and doxorubicin (van Asperen et al., 1999b) has been reported in mice lacking mdr1a Pgp. The Pgp pump is inhibited by reversal agents for MDR; among these are ve- rapamil and amiodarone (Stein, 1997). Indirect evidence for Pgp-mediated transport in the heart has been obtained from an enhancement of cardiac uptake of anthracyclines after combination with Pgp inhibitors (Colombo et al., 1996). This study was designed to characterize the uptake process of idarubicin and to examine the effect of the Pgp antagonists verapamil and amiodarone in the single-pass perfused rat heart. To our knowledge, such a kinetic analysis of cardiac Pgp substrate transport has so far not been reported. The method is based on the measurement of venous outflow con- centration-time profile and contractile response after a 10- min infusion of idarubicin into the inflow. However, the pa- rameters that govern transport mechanisms are not directly observable and can only be obtained using a mathematical model that attempts to describe the disposition kinetics of the drug in the organ. Compartmental modeling quantified some basic features and provided evidence for Michaelis- Menten type uptake and Pgp-mediated influx “hindrance” of idarubicin. Furthermore, by pharmacokinetic/pharmacody- namic modeling cellular kinetics was linked with the time course of negative inotropic response of idarubicin. Thus, information on the functional role of compartments was ob- This work was partially supported by Deutsche Forschungsgemeinschaft (GRK 134/1-96). ABBREVIATIONS: MDR, multiple drug resistance; Pgp, P-glycoprotein; IDA, idarubicin; LVDP, left ventricular developed pressure; SNLR, simultaneous nonlinear regression; CV, coefficient of variation of parameter estimate. 0022-3565/02/3002-688 –694$3.00 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS Vol. 300, No. 2 Copyright © 2002 by The American Society for Pharmacology and Experimental Therapeutics 4493/960591 JPET 300:688–694, 2002 Printed in U.S.A. 688 at ASPET Journals on July 8, 2017 jpet.aspetjournals.org Downloaded from