Research Papers:

Changes in cytochrome P450s-mediated drug clearance in patients with hepatocellular carcinoma in vitro and in vivo: a bottom-up approach

Jie Gao, Jun Zhou, Xiao-Pei He, Yun-Fei Zhang, Na Gao, Xin Tian, Yan Fang, Qiang Wen, Lin-Jing Jia, Han Jin and Hai-Ling Qiao _

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Oncotarget. 2016; 7:28612-28623. https://doi.org/10.18632/oncotarget.8704

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Jie Gao1,*, Jun Zhou1,*, Xiao-Pei He1, Yun-Fei Zhang1, Na Gao1, Xin Tian1, Yan Fang1, Qiang Wen1, Lin-Jing Jia1, Han Jin1, Hai-Ling Qiao1

1Institute of Clinical Pharmacology, Zhengzhou University, Zhengzhou, China

*These authors have contributed equally to this work

Correspondence to:

Hai-Ling Qiao, e-mail: [email protected]

Keywords: hepatocellular carcinoma, bottom up IVIVE approach, hepatic clearance, cytochrome P450s, microsomal protein per gram of liver

Received: February 14, 2016    Accepted: March 27, 2016    Published: April 12, 2016


Hepatocellular carcinoma (HCC) accompanied by severe liver dysfunction is a serious disease, which results in altered hepatic clearance. Generally, maintenance doses depend upon drug clearance, so individual dosage regimens should be customized for HCC patients based on the condition of patients. Based on clearance of CYP isoform-specific substrates at the microsomal level (CLM), microsomal protein per gram of liver (MPPGL), liver weight, hepatic blood flow, hepatic clearance values (CLH) for 10 CYPs in HCC patients (n=102) were extrapolated using a predictive bottom-up pharmacokinetic model. Compared with controls, the CLM values for CYP2C9, 2D6, 2E1 were significantly increased in HCC patients. Additionally, CYP1A2, 2C8, 2C19 CLM values decreased while the values for CYP2A6, 2B6, 3A4/5 were unchanged. The MPPGL values in HCC tissues were significantly reduced. CLH values of HCC patients for CYP1A2, 2A6, 2B6, 2C8, 2C19, and 3A4/5 were significantly reduced, while this for CYP2E1 were markedly increased and those for CYP2C9 and 2D6 did not change. Moreover, disease (fibrosis and cirrhosis) and polymorphisms of the CYP genes have influenced the CLH for some CYPs. Prediction of the effects of HCC on drug clearance may be helpful for the design of clinical studies and the clinical management of drugs in HCC patients.

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