Abstract
Liver cirrhosis is a chronic disease that affects the liver structure, protein expression, and overall metabolic function. Abundance data for drug-metabolizing enzymes and transporters (DMET) across all stages of disease severity are scarce. Levels of these proteins are crucial for the accurate prediction of drug clearance in hepatically impaired patients using physiologically based pharmacokinetic (PBPK) models, which can be used to guide the selection of more precise dosing. This study aimed to experimentally quantify these proteins in human liver samples and assess how they can impact the predictive performance of the PBPK models. We determined the absolute abundance of 51 DMET proteins in human liver microsomes across the three degrees of cirrhosis severity (n = 32; 6 mild, 13 moderate, and 13 severe), compared to histologically normal controls (n = 14), using QconCAT-based targeted proteomics. The results revealed a significant but non-uniform reduction in the abundance of enzymes and transporters, from control, by 30–50% in mild, 40–70% in moderate, and 50–90% in severe cirrhosis groups. Cancer and/or non-alcoholic fatty liver disease-related cirrhosis showed larger deterioration in levels of CYP3A4, 2C8, 2E1, 1A6, UGT2B4/7, CES1, FMO3/5, EPHX1, MGST1/3, BSEP, and OATP2B1 than the cholestasis set. Drug-specific pathways together with non-uniform changes of abundance across the enzymes and transporters under various degrees of cirrhosis necessitate the use of PBPK models. As case examples, such models for repaglinide, dabigatran, and zidovudine were successful in recovering disease-related alterations in drug exposure. In conclusion, the current study provides the biological rationale behind the absence of a single dose adjustment formula for all drugs in cirrhosis and demonstrates the utility of proteomics-informed PBPK modeling for drug-specific dose adjustment in liver cirrhosis.
Highlights
Cirrhosis is a global health burden, accounting for over 1 million deaths per annum, and 4.9 to 9.5% of the global population is believed to have some level of cirrhosis.[1−3] It occurs in late-stage liver fibrosis as a result of different types of liver disease, such as hepatitis, cholestasis, cancer, and alcoholic and non-alcoholic fatty liver disease (NAFLD).[4]
We observed a progressive decline in the abundance of enzymes and transporters with increasing severity of cirrhosis compared to the control livers, in line with the progressive decline in microsomal protein content per gram of liver (MPPGL), which we reported previously.[14]
Several older reports have claimed that phase II reactions are less affected by hepatic impairment (HI) than oxidative phase I reactions.[40−42] We show that the expression of several UGTs, such as UGT1A6, 1A9, 2B4, and 2B7, is significantly impaired by cirrhosis, especially in moderate to severe stages
Summary
Cirrhosis is a global health burden, accounting for over 1 million deaths per annum, and 4.9 to 9.5% of the global population is believed to have some level of cirrhosis.[1−3] It occurs in late-stage liver fibrosis as a result of different types of liver disease, such as hepatitis, cholestasis, cancer, and alcoholic and non-alcoholic fatty liver disease (NAFLD).[4]. Implementation of this recommendation may require time, and alternate approaches, such as the use of physiologically based PK (PBPK) models, are applied for predicting changes in drug exposure and guiding
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