Pharmacokinetics of the cardioprotective drug dexrazoxane and its active metabolite ADR-925 with focus on cardiomyocytes and the heart

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216208%3A11150%2F18%3A10367425" target="_blank" >RIV/00216208:11150/18:10367425 - isvavai.cz</a>

Alternative codes found

RIV/00216208:11160/18:10367425

Result on the web

<a href="http://jpet.aspetjournals.org/content/364/3/433" target="_blank" >http://jpet.aspetjournals.org/content/364/3/433</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1124/jpet.117.244848" target="_blank" >10.1124/jpet.117.244848</a>

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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Type

J_imp - Article in a specialist periodical, which is included in the Web of Science database

CEP classification

—

OECD FORD branch

30104 - Pharmacology and pharmacy

Project

<a href="/en/project/GA13-15008S" target="_blank" >GA13-15008S: New potential cardioprotective agents: study of structure-activity relationships in various types of myocardial injury</a><br>

Continuities

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Publication year

2018

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

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