Scaling Factors for Clearance in Adult Liver Cirrhosis

Abstract

In-vitro in-vivo extrapolation (IVIVE) enables prediction of in vivo clinical outcomes related to drug exposure in various populations from in vitro data. Prudent IVIVE requires scalars specific to the biological characteristics of the system in each population. This study determined experimentally, for the first time, scalars in liver samples from patients with varying degrees of cirrhosis. Microsomal and cytosolic fractions were extracted from 13 noncirrhotic and 32 cirrhotic livers (6 mild, 13 moderate, and 13 severe, based on Child-Pugh Score). Fractional protein content was determined and cytochrome P450 reductase activity was used to correct for microsomal protein loss. Although the median microsomal protein per gram liver (MPPGL) in mild, moderate, and severe cirrhosis (26.2, 32.4, and 30.8 mg.g-1 , respectively) seemed lower than control livers (36.6 mg.g-1), differences were not statistically significant (Kruskal-Wallis test, p>0.05). Corresponding values for cytosolic protein per gram liver (CPPGL) were 88.2, 67.9, 62.2 and 75.4 (mg.g-1) for mild, moderate, sever cirrhosis and control livers, respectively, with statistically lower values for server vs controls (Mann-Whitney p=0.006). Cirrhosis associated with cancer showed lower MPPGL (24.8 mg.g-1) than cirrhosis associated with cholestasis (38.3 mg.g-1 , p=0.003). Physiologicallybased pharmacokinetic simulations with disease-specific scalars captured cirrhosis impact on exposure to afentanil, metoprolol, midazolam, and ethinylestradiol. These experimentallydetermined scalars should alleviate the need for indirect scaling using functional liver volume. Scaling factors in cirrhosis might be a reflection of the etiology rather than the disease severity. Hence, bundling various cirrhotic conditions under the same umbrella when predicting hepatic impairment impact should be revisited. Significance statement: Cirrhosis-specific scalars required for extrapolation from microsomal or cytosolic in vitro systems to liver tissue are lacking. These scalars can help in This article has not been copyedited and formatted. The final version may differ from this version.

Proteomic Quantification of Changes in Abundance of Drug-Metabolizing Enzymes and Drug Transporters in Human Liver Cirrhosis: Different Methods, Similar Outcomes

“…However, these changes are not fully understood and differences can be related to the enzyme isoform, degree of disease severities and underlying conditions (Elbekai, et al, 2004). Using DPF, the degree of change in expression of hepatic enzymes and transporters among cirrhosis samples of different etiologies revealed differences in their pathophysiology and confirmed the heterogeneity of cirrhosis as a disease, in line with previous studies (Drozdzik, et al, 2019;El-Khateeb, et al, 2020;Prasad, et al, 2018). In agreement with our findings, Prasad et al (2018) reported reduced CYP and UGT expression in cirrhosis, although the causes of the disease were different from those explored in the current study.…”

“…Cirrhotic livers were obtained from diseased livers following liver transplantation. Individual liver tissue samples were provided by Cambridge University Hospitals Tissue Bank (Cambridge, UK), and HLM fractions were prepared by differential centrifugation, as described in detail for the same set of samples in a previous publication (El-Khateeb, et al, 2020). The HLM fractions were pooled for each group separately by mixing 6 μL from each individual sample (corresponding to 6 mg of tissue from each liver sample).…”

“…These samples are covered by ethical approval from the Health Research Authority and Health and Care Research Wales (Research Ethics Committee Approval Reference 18/LO/1969). The samples were prepared and analyzed for previous work (El-Khateeb et al, 2020) and the opportunity arose to further use these sets for a comparative investigation of different quantification methods in health and disease.…”

Review article: time to revisit Child‐Pugh score as the basis for predicting drug clearance in hepatic impairment

“…34,35 The simulation outputs for different drugs were in agreement with the biologically determined scalars using microsomal and cytosolic protein contents. 36 These technologies offer promise, but more studies are required to investigate the change in the activities of different DMET against imagerelated measures.…”

“…Moreover, the level of change in the expression and activity of different DMET is not the same across scores and is also affected by the aetiology of the disease and its surrounding environment. 36,53 This can be partly attributed to the fact that the liver is actually not "well-stirred" as usually assumed in different models. The well-stirred model assumes that the liver is a single well-stirred compartment and that the unbound drug concentration in the emergent blood is in equilibrium with the unbound drug within the liver.…”