Modeling the metabolism of idarubicin to idarubicinol in rat heart: effect of rutin and phenobarbital.
Since the severe cardiotoxicity of anthracyclines has been attributed to the intramyocardial formation of C-13 alcohol metabolites, the kinetics of cardiac metabolite formation and disposition as well as the effect of carbonyl reductase inhibitors are of specific interest. This study was designed to investigate the effect of rutin and phenobarbital on the pharmacokinetics of idarubicin (IDA) and its conversion to idarubicinol (IDOL) in the single-pass perfused rat heart. After infusion of IDA (0.5 mg) during 1min, the venous outflow concentrations of IDA and IDOL were measured up to 80 min in the presence and absence of rutin and phenobarbital. A kinetic model was developed to help to interpret the concentration profiles in terms of compartmentation of IDOL formation and to estimate parameters quantitatively descriptive of the transport and biotransformation processes. Rutin and phenobarbital significantly reduced the residual amount of IDOL in heart to 64 and 47% of control, respectively. Pharmacokinetic modeling of the data revealed that IDOL is generated in two different compartments, besides the tissue compartment characterized by saturable uptake, also the compartment that accounts for the quasi-instantaneous initial distribution process is involved. The efflux rate constant of IDOL, k(21,IDOL,) was much smaller than that of IDA. Rutin and phenobarbital significantly reduced IDOL production. Additionally, phenobarbital competitively inhibited the saturable uptake of both IDA and IDOL (increase in apparent Michaelis constants). Reanalysis of data obtained in previous experiments showed that P-glycoprotein inhibitors (verapamil and amiodarone) reduced IDOL uptake in a similar way as already shown for IDA. The present study further supports the utility of pharmacokinetic modeling in identifying sites of drug interactions within the heart.
Kang
Wonku
W
Section of Pharmacokinetics, Department of Pharmacology, Martin Luther University Halle-Wittenberg, 06097 Halle, Germany.
Weiss
Michael
M
D000638:Amiodarone / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism; D003630:Daunorubicin / Q000031:analogs & derivatives* / Q000378:metabolism*; D015195:Drug Design; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D015255:Idarubicin / Q000378:metabolism*; D007700:Kinetics; D008297:Male; D010634:Phenobarbital / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012431:Rutin / Q000494:pharmacology*; D013997:Time Factors; D014665:Vasodilator Agents / Q000494:pharmacology; D014700:Verapamil / Q000494:pharmacology
D000970:Antineoplastic Agents; D018691:Excitatory Amino Acid Antagonists; D014665:Vasodilator Agents; D012431:Rutin; C054440:idarubicinol; D014700:Verapamil; D000638:Amiodarone; D010634:Phenobarbital; D015255:Idarubicin; D003630:Daunorubicin