Interaction of Cytochrome P450 3A4 with Fatty Acid Binding Protein 1 and Relevance to Drug Metabolism

Liver fatty acid binding protein (FABP1) is an abundant cytosolic component that interacts with drugs and can transfer substrates to cytochrome P450 enzymes (P450s, CYPs). FABP1 bound the P450 3A4 substrates diazepam and sulfinpyrazone with <i>K</i>_d values < 2.5 μM. FABP1 weakly attenuated P450 3A4 oxidations of both drugs in two independent assay modes. Reconstitution of human liver microsomes with cytosol attenuated diazepam metabolism but stimulated sulfinpyrazone oxidation, possibly due to GST A1-1. Kinetic modeling of reactions with varying FABP1 and substrate concentrations favored a model of directed substrate transfer to P450 3A4. Kinetic simulations revealed FABP1-dependent inhibition of diazepam oxidation at high physiological concentrations of FABP1, likely due to competition for P450 binding. Consideration of the influence of both P450 and FABP1 on drug metabolism may be critical for accurate modeling and prediction of drug pharmacokinetics.