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

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

doi:10.18632/oncotarget.8704

Abstract

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.

Highlights

Significant research efforts towards the development of personalized medicine have been conducted especially for patients with liver diseases that usually are accompanied by the loss of functional hepatocytes
The most marked increase was the Clearance at microsomal level (CLM) value for CYP2E1, which increased by 99.5%, while the most prominent reduction was the CLM for CYP2C8, which declined by 77%
This represents the first extensive study to test the clearances for 10 Cytochrome P450 (CYP) in vitro and in vivo using 102 liver samples from patients with Hepatocellular carcinoma (HCC) accompanied by fibrosis or cirrhosis

Summary

Introduction

Significant research efforts towards the development of personalized medicine have been conducted especially for patients with liver diseases that usually are accompanied by the loss of functional hepatocytes. Because of the complex pharmacokinetics changes that occur in liver diseases, both the US FDA and European Medicines Agency have released general guidelines that recommend conducting pharmacokinetic studies when drugs are likely to be used in patients with impaired hepatic function. HCC often results in biochemical and physiological changes, such as altered hepatic function, hepatic blood flow (QH), functional liver size, and plasma protein binding. These changes can result in changed clearance compared with what is observed in subjects with normal hepatic function. Maintenance doses depend on drug clearance, so individual dosage regimens should be customized for HCC patients based on the condition of each patient

Methods

Results

Conclusion