5-氟尿嘧啶（5-FU）及其前药卡培他滨是常用的抗肿瘤药物。本研究旨在建立卡培他滨代谢物和5-FU代谢物的生理药动学（PBPK）模型，描述肝损伤癌症患者的肿瘤和血浆中的药物动力学。以PK-Sim®和MoBi®软件为基础，开发了包括癌症区域的模型，并通过25个口服卡培他滨和18个静脉注射5-FU的癌症患者研究的R编程语言进行评估。大多数模拟的Cmax和AUClast值在观察值的两倍误差范围内，成功地构建了PBPK模型。模拟结果显示，在肝功能损伤的癌症患者中，口服卡培他滨后，肿瘤中5-FU的Cmax和AUClast的变化分别为1.956和3.676，而静脉注射5-FU后未观察到显著变化。此外，肿瘤组织中的5-FU浓度随着肿瘤灌注而增加，但与肿瘤大小无关。敏感性分析显示，二氢嘧啶脱氢酶（DPD）和其他代谢酶的活性、卡培他滨在肠道的渗透性和血浆蛋白比例因子在肿瘤和血浆5-FU药动学中起着重要作用。PBPK模型的预测结果表明，肝功能损伤的癌症患者无需调整卡培他滨或5-FU的剂量，但在观察到毒性反应时会有所减少。此外，对于5-FU在肿瘤中的浓度，血流速率而非肿瘤大小至关重要。总之，这些模型可以预测不同场景中具有不同特征的癌症患者肿瘤中5-FU的药代动力学。© 2023. 作者（名）在Springer Science+Business Media, LLC，隶属于Springer Nature的独家许可下发表。

5-fluorouracil (5-FU) and its prodrug capecitabine are commonly prescribed anti-tumor medications. We aimed to establish physiologically based pharmacokinetic (PBPK) models of capecitabine-metabolites and 5-FU-metabolites to describe their pharmacokinetics in tumor and plasma of cancer patients with liver impairment.Models including the cancer compartment were developed in PK-Sim® and MoBi® and evaluated by R programming language with 25 oral capecitabine and 18 intravenous 5-FU studies for cancer patients with and without liver impairment.The PBPK models were constructed successfully as most simulated Cmax and AUClast were within two-fold error of observed values. The simulated alterations of tumor 5-FU Cmax and AUClast in cancer patients with severe liver injury compared with normal liver function were 1.956 and 3.676 after oral administration of capecitabine, but no significant alteration was observed after intravenous injection of 5-FU. Besides, 5-FU concentration in tumor tissue increases with higher tumor blood flow but not tumor size. Sensitivity analysis revealed that dihydropyrimidine dehydrogenase (DPD) and other metabolic enzymes' activity, capecitabine intestinal permeability and plasma protein scale factor played a vital role in tumor and plasma 5-FU pharmacokinetics.PBPK model prediction suggests no dosage adaption of capecitabine or 5-FU is required for cancer patients with hepatic impairment but it would be reduced when the toxic reaction is observed. Furthermore, tumor blood flow rate rather than tumor size is critical for 5-FU concentration in tumor. In summary, these models could predict pharmacokinetics of 5-FU in tumor in cancer patients with varying characteristics in different scenarios.© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.