Influence of P-glycoprotein modulators on cardiac uptake, metabolism, and effects of idarubicin.
OBJECTIVE
The clinical utility of anthracyclines like idarubicin (IDA) is limited by the occurrence of multidrug resistance and cardiotoxicity. Previous studies have demonstrated that the multidrug transporter P-glycoprotein (P-gp) is present in the heart and have suggested that it exerts a protective function. We sought to determine the influence of P-gp inhibitors verapamil and PSC 833 on myocardial uptake, metabolism, and actions of IDA.


METHODS
In Langendorff-perfused rat hearts, the outflow concentration-time curve and the residual amount in cardiac tissue of IDA and its active metabolite idarubicinol (IDOL) were measured after 0.5 mg dose of IDA in the absence and presence of the P-gp inhibitors verapamil and PSC 833.


RESULTS
During perfusion (80 min), 2% of the IDA dose was converted to IDOL in the heart. Myocardial uptake of IDA was significantly increased by verapamil but not by PSC 833, which increased the recovery of IDA and IDOL. IDA significantly decreased left ventricular developed pressure to approximately 40% and increased coronary vascular resistance to 140% of baseline level, respectively. The vasoconstrictive effect was markedly potentiated by PSC 833.


CONCLUSIONS
The enhancement of myocardial IDA uptake by verapamil could be due to a decrease in P-gp-mediated efflux. PSC 833 inhibits cardiac metabolism (non-IDOL pathways) and increases the acute cardiotoxicity of IDA.
Kang
W
W
Section of Pharmacokinetics, Department of Pharmacology, Martin Luther University Halle-Wittenberg, Halle, Germany.
Weiss
M
M
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D000465:Algorithms; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000378:metabolism* / Q000494:pharmacology*; D003524:Cyclosporins / Q000494:pharmacology; D003630:Daunorubicin / Q000031:analogs & derivatives* / Q000378:metabolism; D006321:Heart / Q000187:drug effects*; D015255:Idarubicin / Q000378:metabolism* / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D009206:Myocardium / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013318:Stroke Volume / Q000187:drug effects / Q000502:physiology; D014700:Verapamil / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000903:Antibiotics, Antineoplastic; D003524:Cyclosporins; C054440:idarubicinol; D014700:Verapamil; C070272:valspodar; D015255:Idarubicin; D003630:Daunorubicin