Pharmacokinetics of the Cardioprotective Drug Dexrazoxane and Its Active Metabolite ADR-925 with Focus on Cardiomyocytes and the Heart
Language English Country Netherlands Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
29273587
DOI
10.1124/jpet.117.244848
PII: S0022-3565(24)26175-9
Knihovny.cz E-resources
- 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
- Names of Substances
- Dexrazoxane MeSH
- Ethylenediamines MeSH
- Glycine MeSH
- ICRF 198 MeSH Browser
- Cardiotonic Agents 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.
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