JoVE - Journal of Visualized Experiments
JoVE Visualize
Contact Us

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

  • 0Department of Anesthesiology, Henan Provincial People's Hospital, Zhengzhou, China.
Journal of Gastrointestinal Oncology +

|

March 21, 2025

|

March 21, 2025

View abstract on PubMed

Summary

This summary is machine-generated.

Hepatocellular carcinoma with cirrhosis (HCCC) patients have lower liver microsomal protein content, affecting drug metabolism. Liver tissue clearance (CL<sub>L</sub>) better predicts in vivo hepatic clearance (CL<sub>H</sub>) than microsomal protein level (CL<sub>M</sub>) in HCCC.

Area Of Science

  • Pharmacology
  • Hepatology
  • Drug Metabolism

Background

  • Hepatocellular carcinoma with cirrhosis (HCCC) impacts hepatic drug metabolism, complicating individualized dosing.
  • Microsomal protein per gram of liver (MPPGL) data in HCCC patients is limited, hindering pharmacokinetic modeling.
  • Understanding drug metabolism in HCCC is crucial for optimizing patient treatment.

Purpose Of The Study

  • To determine MPPGL content in HCCC patients.
  • To analyze the activity of 10 cytochrome P450 (CYP) isoforms in HCCC.
  • To guide individualized clinical drug dosing in HCCC using in vitro data.

Main Methods

  • Measured MPPGL in liver samples from HCCC patients (n=48) and controls (n=68).
  • Determined the activity of 10 CYP isoforms at the microsomal protein level (CL<sub>M</sub>).
  • Extrapolated liver tissue clearance (CL<sub>L</sub>) and predicted in vivo hepatic clearance (CL<sub>H</sub>) based on MPPGL and CL<sub>M</sub>.

Main Results

  • MPPGL was significantly lower in HCCC patients (28.35 mg/g) vs. controls (37.65 mg/g) (P=0.008).
  • CL<sub>M</sub> of CYP1A2, CYP2C8, CYP2C19 decreased; CYP2D6, CYP2E1 increased in HCCC. CYP2A6, CYP2B6, CYP2C9, CYP3A4/5 showed no significant change.
  • CL<sub>L</sub> changes were inconsistent with CL<sub>M</sub>; CL<sub>L</sub> strongly correlated with CL<sub>H</sub> (median Spearman r=0.9868).

Conclusions

  • HCCC patients exhibit reduced MPPGL and variable CYP activity in microsomes.
  • CL<sub>L</sub>, accounting for individual MPPGL, better reflects in vitro CYP metabolism than CL<sub>M</sub>.
  • The strong correlation between CL<sub>L</sub> and CL<sub>H</sub> offers value for clinical drug management in HCCC.

Keywords: