Zhou Jun, Gao Na, Tian Xin, Fang Yan, Gao Jie, Wen Qiang, Cui Ming-Zhu, Zhang Yun-Fei, Li Sai-Fei, Jia Lin-Jing, Qiao Hai-Ling
Department of Anesthesiology, Henan Provincial People's Hospital, Zhengzhou, China.
Institute of Clinical Pharmacology, Zhengzhou University, Zhengzhou, China.
J Gastrointest Oncol. 2025 Feb 28;16(1):146-158. doi: 10.21037/jgo-2024-963. Epub 2025 Feb 24.
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 drug metabolism data.
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) was determined. According to the value of MPPGL and CL, the activity of CYPs in the liver tissue clearance (CL) and predicted hepatic clearance (CL) were extrapolated.
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 of CYP1A2, CYP2C8, and CYP2C19 was significantly decreased while that of CYP2D6 and CYP2E1 was significantly increased; meanwhile, the CL of CYP2A6, CYP2B6, CYP2C9, and CYP3A4/5 was not significantly changed. The changes in CL were not consistent with those in CL among patients with HCCC. The median spearman rank correlation coefficient was 0.7880±0.079 between CL and CL and was 0.9868±0.022 between CL and CL for the 10 CYPs (P<0.001).
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 is better suited than CL to represent the metabolism of CYPs, with the strongest correlation being observed between CL and CL. This finding holds potential value for guiding clinical management of drugs in patients with HCCC.
肝细胞癌合并肝硬化（HCCC）患者的肝脏代谢可能与无肝硬化的肝细胞癌（HCC）患者不同，这限制了这些患者的临床个体化给药方案。每克肝脏微粒体蛋白（MPPGL）是基于生理的药代动力学模型的一个重要缩放因子，但HCCC患者的数据有限。本研究旨在确定HCCC患者的MPPGL含量，并利用药物代谢数据指导HCCC患者的个体化临床给药。
测定了HCCC患者（n = 48）肝脏样本和正常肝脏样本（n = 68）中的微粒体蛋白含量。测定了10种细胞色素P450（CYP）同工酶在微粒体蛋白水平（CL）的活性。根据MPPGL和CL的值，外推肝脏组织清除率（CL）和预测肝脏清除率（CL）中CYPs的活性。
HCCC患者的MPPGL中位数（28.35 mg/g）显著低于对照组（37.65 mg/g）（P = 0.008）。与对照组相比，HCCC患者中CYP1A2、CYP2C8和CYP2C19的CL显著降低，而CYP2D6和CYP2E1的CL显著升高；同时，CYP2A6、CYP2B6、CYP2C9和CYP3A4/5的CL无显著变化。HCCC患者中CL的变化与CL的变化不一致。10种CYPs的CL与CL之间的中位数斯皮尔曼等级相关系数为0.7880±0.079，CL与CL之间的为0.9868±0.022（P < 0.001）。
在HCCC患者中，MPPGL含量显著降低，微粒体中10种CYP的活性出现可变变化。考虑个体MPPGL时，CL比CL更适合代表CYPs的代谢，CL与CL之间的相关性最强。这一发现对指导HCCC患者的临床药物管理具有潜在价值。
