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

Abstract

This article is available online at http://dmd.aspetjournals.org ABSTRACT: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 Pglycoprotein 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.

Scutellarin protects against doxorubicin-induced acute cardiotoxicity and regulates its accumulation in the heart

“…Quercetin has better cardioprotective effects against DOX cardiotoxicity, and it could significantly inhibit the metabolic conversion of DOX to doxorubicinol (Vaclavikova et al 2008 ). The aldo–keto reductase inhibitors phenobarbital and rutin also could alter the metabolism, pharmacokinetics, and toxicity of anthracycline (Behnia and Boroujerdi 1999 ; Kang and Weiss 2003 ). However, it has not been reported that flavonoids can diminish heart exposure to DOX.…”

A Heart‐Breast Cancer‐on‐a‐Chip Platform for Disease Modeling and Monitoring of Cardiotoxicity Induced by Cancer Chemotherapy

“…[ 39 ] Therefore, for simulating DOX concentration over the bioreactors, the aforementioned Equations () and () were used and the corresponding parameters were accordingly extracted from the literature. [ 37–39,52,53 ]…”

Anthracyclines: Molecular Advances and Pharmacologic Developments in Antitumor Activity and Cardiotoxicity

“…In this respect, recent studies conducted by perfusing rat heart with IDA have shown that a major pool of IDAol would be formed in the vascular wall rather than in cardiomyocytes, transiently increasing coronary resistance rather than inducing negative inotropism (Kang and Weiss, 2003). These findings indicate that an additional determinant of cardiac toxicity or tolerability pertains to the compartment within which alcohol metabolites are formed and suggest that anthracyclines undergoing metabolization in cellular types other than cardiomyocytes might prove to induce different patterns of cardiotoxicity compared with anthracyclines' exhibiting preferred metabolization in the vulnerable myocytes.…”