Cyclosporin increases cellular idarubicin and idarubicinol concentrations in relapsed or refractory AML mainly due to reduced systemic clearance

Smeets, M.E.P.; Raymakers, R.A.P.; Muus, Petra; Vierwinden, G.; Linssen, P.C.M.; Masereeuw, Rosalinde; Witte, T.J.M. de

doi:10.1038/sj.leu.2401996

Cited by 20 publications

(2 citation statements)

References 55 publications

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“…Fourth, the enhancement of the IDOL re-uptake into Compartment 2 by the P-glycoprotein inhibitors verapamil and amiodarone (increase in V max ) is similar to that reported for IDA (Weiss and Kang, 2002). This is in principal accordance with the action of multidrug resistant modulators on IDOL concentration in tumor cells (Schroder et al, 2000;Smeets et al, 2001) and suggests that P-glycoprotein inhibitors may also enhance the cardiac accumulation of IDOL. The physiologic role of cardiac P-glycoprotein expression and pharmacokinetic consequences of P-glycoprotein inhibition have been addressed previously (Weiss and Kang, 2002; and the references cited therein).…”

Section: Myocardial Metabolism Of Idarubicin To Idarubicinolsupporting

confidence: 78%

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

Kang¹,

Weiß²

2003

Drug Metab Dispos

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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.

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Section: Myocardial Metabolism Of Idarubicin To Idarubicinolsupporting

confidence: 78%

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

Kang¹,

Weiß²

2003

Drug Metab Dispos

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“…Most clinical trials in adults and children have demonstrated the enhanced potency of IDA over DNR in remission induction (33–36). Some studies have suggested that IDA efficacy is further improved in the presence of MDR modulators (37–41). In view of the results from our study, further clinical trials are warranted that combine MDR modulators with IDA in less toxic regimens (42).…”

Section: Discussionmentioning

confidence: 99%

Modulation of resistance to idarubicin by the cyclosporin PSC 833 (valspodar) in multidrug‐resistant cells

Lacayo

Durán²,

Šikić³

2003

J Exp Therapeutics

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Idarubicin (IDA) is an anthracycline anticancer drug utilized in the treatment of acute leukemias. There are conflicting data published with regard to the cross-resistance of IDA in multidrug-resistant (MDR) cells expressing P-glycoprotein (P-gp). We evaluated the cytotoxicity and cellular accumulation of IDA in a panel of anthracycline-selected MDR cell lines. Leukemia K562/R7 cells and sarcoma MES-SA/Dx5 cells expressing high levels of the MDR1 (ABCB1) gene were resistant to IDA (42-fold and 150-fold, respectively). In both of these cell lines, resistance to IDA was equivalent to that for doxorubicin, the drug used to select for the MDR variants. The P-gp inhibitor PSC 833 (valspodar) at 2 microM completely restored sensitivity to IDA. IDA accumulation was decreased 12-fold in MES-SA/Dx5 cells vs parental cell line, and drug uptake was restored to control levels by PSC 833. Reduced intracellular IDA was correlated with P-gp content by flow cytometry. Experiments in NIH3T3 murine cells transfected with the human MDR1 gene substantiated the findings of cross-resistance to IDA and reversal of resistance by PSC 833. Our data indicate that IDA is a high-affinity substrate for P-gp.

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Introduction to Drug Transporters

Leung¹,

Oganesian²

2008

Drug Metabolism Handbook

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Cyclosporin increases cellular idarubicin and idarubicinol concentrations in relapsed or refractory AML mainly due to reduced systemic clearance

Cited by 20 publications

References 55 publications

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

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

Modulation of resistance to idarubicin by the cyclosporin PSC 833 (valspodar) in multidrug‐resistant cells

Introduction to Drug Transporters

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