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

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/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 (K m ϭ 3.06 M, V max ϭ 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 amiodarone attenuated the negative inotropic action of idarubicin, which was linked to the intracellular concentration of idarubicin.

Modeling the Metabolism of Idarubicin to Idarubicinol in Rat Heart: Effect of Rutin and Phenobarbital

“…The active transport with Michaelis-Menten type kinetics is characterized by the apparent maximal transport rates V max,12 and the apparent Michaelis constant K M,12 , and the k ij denote first order rate constants describing passive intercompartmental transport. Since the time course IDA 2 (t) was closely related to its pharmacodynamics (negative inotropy), it has been suggested that Compartment 2 reflects distribution in cardiomyocytes (Weiss and Kang, 2002). The rate constant k 24 accounts for cellular sequestration (irreversible binding and/or conversion to IDA aglycone).…”

“…The structure of the model and the parameters accounting for the disposition of IDA were then fixed in fitting an extended model to the outflow concentration profile of the formed IDOL. Thereby, we used the ADAPT II software package (D'Argenio and Schumitzky, 1997) and a modeling methodology that has been described in detail previously (Weiss and Kang, 2002). Since especially for nonlinear systems the information content of one experiment may be insufficient to resolve the parameters into a unique set of most probable values, we took advantage of the fact that three data sets stem from different but related experiments, the modeling function of which shares one or more parameters.…”

“…We started data analysis using the compartmental model, which describes IDA disposition for the 10-min infusion experiment (Weiss and Kang, 2002) to the outflow data of IDA measured for the injection of 0.5 mg IDA in 1 min. Since only the kinetic data were fitted, the model could be simplified by replacing the (intracellular) saturable transport process from Compartment 2 to Compartment 3 by a passive one [i.e., rate constant k 23 (Kang and Weiss, 2003)].…”

“…One aspect of studies on intact organs is that direct measurements of intramyocardial drug concentrations are difficult to perform; the functional characterization of cardiac IDOL kinetics and its localization requires a mathematical model. We recently developed a compartmental model that is capable of describing the uptake and disposition kinetics of IDA in the isolated rat heart for a 10 min infusion profile (Weiss and Kang, 2002). The concentrationdependent uptake, along with the temperature-dependent transport (Kang and Weiss, 2003) suggested the presence of a specific mechanism that could be described by Michaelis-Menten-type kinetics.…”

“…The present study was undertaken 1) to extend this model by inclusion of the production and disposition kinetics of IDOL, 2) to analyze venous outflow curves of IDA and IDOL following infusion of IDA, 3) to investigate the effect of the carbonyl reductase inhibitors rutin and phenobarbital on the conversion of IDA to IDOL in the heart, and 4) to apply this model to previously published data to examine the influence of P-glycoprotein (P-gp) inhibitors verapamil and amiodarone on the myocardial kinetics of IDOL (Weiss and Kang, 2002). The combined model approach uses kinetic analysis of both IDA and IDOL kinetics to estimate the parameters describing the formation and disposition of IDOL in the heart.…”