Pharmacokinetics of the cardioprotective drug dexrazoxane and its active metabolite ADR-925 with focus on cardiomyocytes and the heart
Result description
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.
Keywords
pharmacokineticsmetabolite kineticsdrug metabolismcardiovascular drugs
The result's identifiers
Result code in IS VaVaI
Alternative codes found
RIV/00216208:11160/18:10367425
Result on the web
DOI - Digital Object Identifier
Alternative languages
Result language
angličtina
Original language name
Pharmacokinetics of the cardioprotective drug dexrazoxane and its active metabolite ADR-925 with focus on cardiomyocytes and the heart
Original language description
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.
Czech name
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Czech description
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Classification
Type
Jimp - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
—
OECD FORD branch
30104 - Pharmacology and pharmacy
Result continuities
Project
Continuities
P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)
Others
Publication year
2018
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Data specific for result type
Name of the periodical
Journal of Pharmacology and Experimental Therapeutics
ISSN
0022-3565
e-ISSN
—
Volume of the periodical
364
Issue of the periodical within the volume
3
Country of publishing house
US - UNITED STATES
Number of pages
14
Pages from-to
433-446
UT code for WoS article
000427302000007
EID of the result in the Scopus database
2-s2.0-85041687174
Result type
Jimp - Article in a specialist periodical, which is included in the Web of Science database
OECD FORD
Pharmacology and pharmacy
Year of implementation
2018