Liver microsomal protein content and activity in patients with hepatocellular carcinoma and cirrhosis: implications for the in vivo prediction of individual hepatic clearance.

Abstract

Background: The hepatic metabolism of patients with hepatocellular carcinoma and cirrhosis (HCCC) may differ from that of patients with hepatocellular carcinoma (HCC) without cirrhosis, limiting the clinical individualized dosing regimens for these patients. Microsomal protein per gram of liver (MPPGL) is an important scaling factor for physiologically based pharmacokinetic models, but data in patients with HCCC are limited. The study aims to determine the content of MPPGL in patients with HCCC and to guide individualized clinical dosing of patients with HCCC using in vitro drug metabolism data.

Methods: The microsomal protein content was determined in liver samples of patients with HCCC (n=48) and in normal liver samples (n=68). The activity of 10 cytochrome P450 (CYP) isoforms at the microsomal protein level (CL_M) was determined. According to the value of MPPGL and CL_M, the activity of CYPs in the liver tissue clearance (CL_L) and predicted in vivo hepatic clearance (CL_H) were extrapolated.

Results: The median value of MPPGL was significantly lower in patients with HCCC (28.35 mg/g) than in the controls (37.65 mg/g) (P=0.008). In patients with HCCC as compared to controls, the CL_M of CYP1A2, CYP2C8, and CYP2C19 was significantly decreased while that of CYP2D6 and CYP2E1 was significantly increased; meanwhile, the CL_M of CYP2A6, CYP2B6, CYP2C9, and CYP3A4/5 was not significantly changed. The changes in CL_L were not consistent with those in CL_M among patients with HCCC. The median spearman rank correlation coefficient was 0.7880±0.079 between CL_H and CL_M and was 0.9868±0.022 between CL_H and CL_L for the 10 CYPs (P<0.001).

Conclusions: In patients with HCCC, MPPGL content was significantly reduced, and a variable change in the activity of 10 CYP was observed in microsomes. When taking individual MPPGL into account, CL_L is better suited than CL_M to represent the in vitro metabolism of CYPs, with the strongest correlation being observed between CL_L and in vivo CL_H. This finding holds potential value for guiding clinical management of drugs in patients with HCCC.