Department of Pharmacology, Faculty of Medicine in Hradec Králové (E.J., J.C., O.L., Z.P., P.B., M.Š.), and Departments of Biochemical Sciences (E.J., A.J., T.Š.), Pharmaceutical Chemistry and Pharmaceutical Analysis (J.B., J.S., P.K.), and Inorganic and Organic Chemistry (G.K., J.R.), Faculty of Pharmacy in Hradec Králové, Charles University, Hradec Králové, Czech Republic.
Department of Pharmacology, Faculty of Medicine in Hradec Králové (E.J., J.C., O.L., Z.P., P.B., M.Š.), and Departments of Biochemical Sciences (E.J., A.J., T.Š.), Pharmaceutical Chemistry and Pharmaceutical Analysis (J.B., J.S., P.K.), and Inorganic and Organic Chemistry (G.K., J.R.), Faculty of Pharmacy in Hradec Králové, Charles University, Hradec Králové, Czech Republic
J Pharmacol Exp Ther. 2018 Mar;364(3):433-446. doi: 10.1124/jpet.117.244848. Epub 2017 Dec 22.
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.
地拉佐辛（DEX）是唯一一种获批用于预防蒽环类药物心脏毒性的心脏保护剂，传统上被认为是铁螯合代谢物 ADR-925 的前体药物。然而，两种药物的药代动力学特征，特别是对其作用至关重要的细胞和组织（心肌细胞/心肌），仍知之甚少。本研究旨在在明确 DEX 具有预防蒽环类药物心脏毒性的情况下，在体外（原代心肌细胞）和体内（兔子）条件下，对 DEX 转化为 ADR-925 的情况进行特征描述。我们的结果表明，DEX 在细胞培养基中可独立于心肌细胞或其裂解物的存在而被水解为 ADR-925。此外，ADR-925 可通过主动转运直接进入细胞，并且可检测到的浓度比 DEX 孵育后更早出现。在兔子中，DEX 给药后 ADR-925 迅速在血浆中检测到，此后形成持续浓度。ADR-925 在心肌中未明显蓄积，其相对暴露量比 DEX 低 5.7 倍。与肝组织不同，心肌匀浆在体外不能加速 DEX 向 ADR-925 的转化，这表明体内心肌浓度可能源自其从中央室的分布。通过非房室分析和群体药代动力学（包括联合亲代-代谢物模型）确定了 DEX 和 ADR-925 的药代动力学参数。重要的是，所有确定的参数都更接近人类数据，而不是啮齿动物数据。这些结果为直接评估 ADR-925 在体外和体内的心脏保护作用开辟了道路，以确定 DEX 是药物还是前体药物。
