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首页> 外文期刊>Biopharmaceutics and Drug Disposition >Investigation of 5-FU disposition after oral administration of capecitabine, a triple-prodrug of 5-FU, using a physiologically based pharmacokinetic model in a human cancer xenograft model: comparison of the simulated 5-FU exposures in the tumour tis
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Investigation of 5-FU disposition after oral administration of capecitabine, a triple-prodrug of 5-FU, using a physiologically based pharmacokinetic model in a human cancer xenograft model: comparison of the simulated 5-FU exposures in the tumour tis

机译：在人类癌症异种移植模型中使用基于生理学的药代动力学模型研究口服卡培他滨（一种5-FU的三药）后的5-FU处置：模拟肿瘤中5-FU暴露的比较

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The nonlinear pharmacokinetics of capecitabine, a triple prodrug of 5-FU preferentially activated in tumour tissues, was investigated in human cancer xenograft models. A physiologically based pharmacokinetic (PBPK) model integrating the activation process of capecitabine to 5-FU and 5-FU elimination was constructed to describe the concentration/time profiles of capecitabine and its three metabolites, including 5-FU, in blood and organs. All the biochemical parameters (enzyme kinetic parameters, plasma protein binding and tissue binding of capecitabine and its metabolites) integrated in this model were measured in vitro. The simulated curves for the blood and tumour concentrations of capecitabine and its metabolites can basically describe the observed values. A simple prodrug of 5-FU, doxifluridine, is known to be activated to 5-FU to some extent in the gastrointestinal (GI) tract, causing diarrhoea, which is the dose limiting side effect of doxifluridine. Consequently, the therapeutic index (the ratio of 5-FU AUC in the tumour to that in GI) after the administration of effective dose capecitabine was predicted by this PBPK model and found to be five times and 3000 times greater than that of doxifluridine and 5-FU, respectively. This was compatible with the previous result for the difference in the ratio of the toxic dose to the minimum effective dose between capecitabine and doxifluridine, suggesting that 5-FU preferentially accumulates in tumour tissue after oral administration of capecitabine compared with the other drugs (doxifluridine and 5-FU). The 5-FU AUC in tumour tissue of human cancer xenograft models at the minimum effective dose was comparable with those estimated for humans at the clinical dose. In addition, the predicted therapeutic indices at the respective doses were correlated well between humans and mice (xenograft model). These results suggest that the 5-FU AUC in human tumour tissue at its clinically effective dose can be predicted based on the PBPK model inasmuch as the 5-FU AUC in a human cancer xenograft model at its effective dose may be measured or simulated. Copyright 2001 John Wiley & Sons, Ltd.
机译：在人类癌症异种移植模型中研究了卡培他滨（一种在肿瘤组织中优先激活的5-FU的三重前药）的非线性药代动力学。建立了结合卡培他滨激活5-FU和消除5-FU的活化过程的基于生理的药代动力学（PBPK）模型，以描述卡培他滨及其三种代谢物（包括5-FU）在血液和器官中的浓度/时间分布。体外测量该模型中整合的所有生化参数（酶动力学参数，血浆蛋白结合和卡培他滨及其代谢产物的组织结合）。卡培他滨及其代谢产物的血液和肿瘤浓度的模拟曲线可以基本描述观察值。已知5-FU的简单前药多西氟啶在胃肠道（GI）中被激活至5-FU一定程度，引起腹泻，这是多西氟啶的剂量限制性副作用。因此，通过该PBPK模型预测了有效剂量卡培他滨给药后的治疗指数（肿瘤中5-FU AUC与GI的比率），发现其比多西氟啶和5分别大5倍和3000倍。 -FU，分别。这与以前的结果相符，即卡培他滨和多西氟啶之间的毒性剂量与最小有效剂量之比不同，这表明与其他药物（多西氟哌啶和多西氟哌啶）相比，口服卡培他滨后5-FU优先在肿瘤组织中蓄积。 5-FU）。最小有效剂量的人类癌症异种移植模型的肿瘤组织中的5-FU AUC与临床剂量的人类估计值相当。另外，在人和小鼠之间（异种移植模型），各个剂量下的预测治疗指数之间具有很好的相关性。这些结果表明，可以基于PBPK模型预测人肿瘤组织中临床有效剂量的5-FU AUC，因为可以测量或模拟人癌异种移植模型中5-FU AUC的有效剂量。版权所有2001 John Wiley＆Sons，Ltd.

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