Caffeine enhances myocardial uptake of idarubicin but reverses its negative inotropic effect.
Idarubicin (IDA) is a member of an important class of anticancer agents, the anthracycline antibiotics. Although the clinical efficacy of anthracyclines is limited by a high incidence of severe cardiac toxicity, our understanding of IDA transport into the heart is still limited. In a previous study, we demonstrated that IDA is transported into the heart by a saturable mechanism. Based on in vitro data suggesting an enhancement by methylxanthines of IDA influx in leukemia cells, this study was designed to test the hypothesis that a commonly used methylxanthine, caffeine, might influence the myocardial uptake of IDA. In the Langendorff rat heart, after infusion of 0.5 mg IDA during 10 min, the presence of caffeine (1 microM) in perfusate enhanced the residual amount of IDA in the heart by 30% due to a 2.7-fold increase in the maximal uptake rate V(max). Theophylline (3 micro M), in contrast, did not influence the uptake process but caused a slight decrease of fractional myocardial sequestration rate (19% reduction). Caffeine reversed the cardiodepressive action of IDA (49% decrease in left ventricular developed pressure at the end of infusion) to a positive inotropic effect (18% increase of basal level). Theophylline significantly attenuated the negative inotropic effect of IDA (only 21% decrease) and led to positive inotropism in the washout phase (21% increase at the end of experiment). We speculate that co-administration of caffeine may enhance the chronic cardiotoxicity of IDA by increasing its accumulation in the heart.
Kang
Wonku
W
Department of Pharmacology, Martin Luther University Halle-Wittenberg, 06097, Halle, Germany.
Weiss
Michael
M
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000009:adverse effects / Q000493:pharmacokinetics*; D002110:Caffeine / Q000494:pharmacology*; D004347:Drug Interactions; D006339:Heart Rate / Q000187:drug effects; D015255:Idarubicin / Q000009:adverse effects / Q000493:pharmacokinetics*; D066298:In Vitro Techniques; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013806:Theophylline / Q000494:pharmacology; D014655:Vascular Resistance / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology*; D016277:Ventricular Function, Left / Q000187:drug effects; D017725:Ventricular Pressure / Q000187:drug effects
D000903:Antibiotics, Antineoplastic; D014665:Vasodilator Agents; D002110:Caffeine; D013806:Theophylline; D015255:Idarubicin