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Pharmacokinetics of the Cardioprotective Drug Dexrazoxane and Its Active Metabolite ADR-925 with Focus on Cardiomyocytes and the Heart
E. Jirkovský, A. Jirkovská, J. Bureš, J. Chládek, O. Lenčová, J. Stariat, Z. Pokorná, G. Karabanovich, J. Roh, P. Brázdová, T. Šimůnek, P. Kovaříková, M. Štěrba,
The Journal of pharmacology and experimental therapeutics.
2018 ;
364 (3) :
433-446.
[pub] 20171222
Language English Country United States
Document type Journal Article, Research Support, Non-U.S. Gov't
Persistent link
https://www.medvik.cz/link/bmc19028652
- MeSH
- Dexrazoxane blood metabolism pharmacokinetics urine MeSH
- Ethylenediamines metabolism pharmacokinetics MeSH
- Glycine analogs & derivatives metabolism pharmacokinetics MeSH
- Myocytes, Cardiac metabolism MeSH
- Cardiotonic Agents blood metabolism pharmacokinetics pharmacology MeSH
- Rabbits MeSH
- Rats MeSH
- Tissue Distribution MeSH
- Animals MeSH
- Check Tag
- Rabbits MeSH
- Rats MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
Dexrazoxane (DEX), the only cardioprotectant approved against anthracycline cardiotoxicity, has been traditionally deemed to be a prodrug of the iron-chelating metabolite ADR-925. However, pharmacokinetic profile of both agents, particularly with respect to the cells and tissues essential for its action (cardiomyocytes/myocardium), remains poorly understood. The aim of this study is to characterize the conversion and disposition of DEX to ADR-925 in vitro (primary cardiomyocytes) and in vivo (rabbits) under conditions where DEX is clearly cardioprotective against anthracycline cardiotoxicity. Our results show that DEX is hydrolyzed to ADR-925 in cell media independently of the presence of cardiomyocytes or their lysate. Furthermore, ADR-925 directly penetrates into the cells with contribution of active transport, and detectable concentrations occur earlier than after DEX incubation. In rabbits, ADR-925 was detected rapidly in plasma after DEX administration to form sustained concentrations thereafter. ADR-925 was not markedly retained in the myocardium, and its relative exposure was 5.7-fold lower than for DEX. Unlike liver tissue, myocardium homogenates did not accelerate the conversion of DEX to ADR-925 in vitro, suggesting that myocardial concentrations in vivo may originate from its distribution from the central compartment. The pharmacokinetic parameters for both DEX and ADR-925 were determined by both noncompartmental analyses and population pharmacokinetics (including joint parent-metabolite model). Importantly, all determined parameters were closer to human than to rodent data. The present results open venues for the direct assessment of the cardioprotective effects of ADR-925 in vitro and in vivo to establish whether DEX is a drug or prodrug.
References provided by Crossref.org
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