Date of Original Version
Biomedical and Pharmaceutical Sciences
Model-based assessment of drug pharmacokinetics in liver disease requires quantification of abundance and disease-related changes in hepatic enzymes and transporters. This study aimed to assess performance of three label-free methods [high N (HiN), intensity-based absolute quantification (iBAQ) and total protein approach (TPA)] against QconCAT-based targeted data in healthy and diseased (cancer and cirrhosis) liver tissue. Measurements were compared across methods and disease-to-control ratios provided a ‘disease perturbation factor’ (DPF) for each protein. Mean label-free measurements of targets correlated well (Pearson's coefficient, r = 0.91–0.98 p < 0.001) and with targeted data (r = 0.65–0.95, p < 0.001). Concordance with targeted data was generally moderate (Lin's concordance coefficient, ρc = 0.46–0.92), depending on methodology. Moderate precision and accuracy were observed for label-free methods (average fold error, AFE = 1.44–1.68; absolute average fold error, AAFE = 2.44–3.23). The DPF reconciled the data and indicated downregulated expression in cancer and cirrhosis, consistent with an inflammatory effect. HiN estimated perturbation consistently with targeted data (AFEHiN = 1.07, AAFEHiN = 1.57), whereas iBAQ overestimated (AFEiBAQ = 0.81, AAFEiBAQ = 1.67) and TPA underestimated (AFETPA = 1.37, AAFETPA = 1.65) disease effect. Progression from mild to severe cirrhosis was consistent with progressive decline in expression, reproduced by HiN but overestimated by iBAQ and underestimated by TPA (AFEHiN = 0.98, AFEiBAQ = 0.60, AFETPA = 1.24). DPF data confirmed non-uniform disease effect on drug-elimination pathways and progressive impact of disease severity.
Publication Title, e.g., Journal
Journal of Proteomics
Vasilogianni, A.-M., El-Khateeb, E., Al-Majdoub, Z. M., Alrubia, S., Rostami-Hodjegan, A., Barber, J., & Achour, B. (2022). Proteomic quantification of perturbation to pharmacokinetic target proteins in liver disease. Journal of Proteomics, 263, 104601. https://doi.org/10.1016/j.jprot.2022.104601
Available at: https://doi.org/10.1016/j.jprot.2022.104601
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