A Multiscale Physiologically-Based Pharmacokinetic Model for Doxorubicin to Explore its Mechanisms of Cytotoxicity and Cardiotoxicity in Human Physiological Contexts.
A Multiscale Physiologically-Based Pharmacokinetic Model for Doxorubicin to Explore its Mechanisms of Cytotoxicity and Cardiotoxicity in Human Physiological Contexts.
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DOI：
10.1007/s11095-018-2456-8
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发表时间：
2018-07-09
影响因子：
3.7
通讯作者：
Cao Y
中科院分区：
文献类型：
--
作者：
He H;Liu C;Wu Y;Zhang X;Fan J;Cao Y
阿霉素细胞毒性和心脏毒性的机制已被广泛探讨，但仍不完全清楚。开发了多尺度生理药代动力学（PBPK）模型，以评估多柔比星在系统、组织间质、细胞和细胞器水平的处置。采用该模型探索阿霉素在人体中的作用机制/毒性。PBPK模型是通过分析小鼠的数据开发的，该模型通过按比例放大以预测大鼠和人类中多柔比星的多尺度分布来验证。详细模拟了阿霉素在人体心脏和肿瘤中的多尺度分布，以阐明其细胞毒性和心脏毒性的潜在机制。所开发的PBPK模型能够充分描述小鼠、大鼠和人中的阿霉素处置。在人体中，延长输注（一种心脏毒性较低的给药方案）预测人体心脏内膜游离阿霉素浓度大幅降低，低于与氧化应激相关的浓度。然而，延长输注不会减少肿瘤细胞核处的阿霉素-DNA加合物，这与临床观察结果一致，即延长输注不会损害抗肿瘤作用，表明一种主要的抗肿瘤机制是DNA扭转。多柔比星的多尺度PBPK模型的开发和进一步应用，以探讨其细胞毒性和心脏毒性机制。
The mechanisms underlying doxorubicin cytotoxicity and cardiotoxicity were broadly explored but remain incompletely understood. A multiscale physiologically-based pharmacokinetic (PBPK) model was developed to assess doxorubicin dispositions at levels of system, tissue interstitial, cell, and cellular organelles. This model was adopted to explore the mechanisms-of-action/toxicity of doxorubicin in humans. The PBPK model was developed by analyzing data from mice and the model was verified by scaling up to predict doxorubicin multiscale dispositions in rats and humans. The multiscale dispositions of doxorubicin in human heart and tumors were explicitly simulated to elucidate the potential mechanisms of its cytotoxicity and cardiotoxicity. The developed PBPK model was able to adequately describe doxorubicin dispositions in mice, rats and humans. In humans, prolonged infusion, a dosing regimen with less cardiotoxicity, was predicted with substantially reduced free doxorubicin concentrations at human heart interstitium, which were lower than the concentrations associated with oxidative stress. However, prolonged infusion did not reduce doxorubicin-DNA adduct at tumor nucleus, consistent with clinical observations that prolonged infusion did not compromise anti-tumor effect, indicating that one primary anti-tumor mechanism was DNA torsion. A multiscale PBPK model for doxorubicin was developed and further applied to explore its cytotoxic and cardiotoxic mechanisms.
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影响因子：
3.5
作者：
Lu, WL;Qi, XR;Wei, SL
通讯作者：
Wei, SL
影响因子：
3.5
作者：
Hendriks, B. S.;Reynolds, J. G.;Wickham, T. J.
通讯作者：
Wickham, T. J.
影响因子：
45.3
作者：
MROSS, K;MAESSEN, P;PINEDO, HM
通讯作者：
PINEDO, HM
影响因子：
0.9
作者：
Becelli, Roberto;Renzi, Giancarlo;Altieri, Fabio
通讯作者：
Altieri, Fabio
影响因子：
3
作者：
JOHANSEN, PB
通讯作者：
JOHANSEN, PB