Liver Fatty Acid Binding Protein (FABP1) Affects Cytochrome P450 2C9 (CYP2C9)-Mediated Metabolism in Human Liver Models

Metabolic clearance of drugs is often systematically over- or underpredicted from human liver microsomes (HLM). We hypothesized that lack of consideration of interactions of cytosolic liver fatty acid binding protein (FABP1) with drugs and cytochrome P450s (CYPs) explains the off-prediction. We used two CYP2C9 probe substrates, diclofenac and tolbutamide, to test this hypothesis. We found that presence of FABP1 alters the kinetics of metabolite formation in HLM. The model that best fit the kinetic data included FABP1-CYP2C9 protein-protein interactions. Statistical modeling of proteomic expression and drug hydroxylation across a panel of 61 human liver S9 fractions (HLS9) showed that CYP2C9 and FABP1 expression together best predicted probe substrate hydroxylation. Incorporation of FABP1 expression and protein-protein interactions into novel physiologically based liver models significantly improved the quantitative accuracy of in vivo hepatic clearance prediction. Together, our data demonstrate the importance of taking FABP1 into consideration for CYP2C9-mediated metabolism.