Modeling Metabolite Kinetics with a Partial Differential Equation-Based Hepatic Sinusoidal Model and MALDI-Mass Spectrometry Imaging of Verapamil and Its Metabolites

A partial differential-equation-based liver model incorporating sinusoidal blood flow, interstitial fluid, cytosol, and lipid partitioning was developed. Reported multi-indicator dilution data were used to parametrize the model, which was interfaced to whole-body compartmental models and was stable for long simulation times. Using intrinsic clearances from the dispersion model with closed boundary conditions, the model reproduces <i>C</i>-<i>t</i> profiles from standard compartmental models. Any property along the sinusoid can be incorporated, including variation in the intrinsic clearance (enzyme zonation). Spatial distribution of verapamil and its metabolites in rat liver was obtained using MALDI-mass spectrometry imaging and was used to evaluate sinusoidal zonation of drug-metabolizing enzymes. Consistent with previous reports, the observed decrease in the sinusoidal verapamil concentration toward the central vein is consistent with increasing intrinsic clearance along the sinusoid. Incorporation of microphysiology and zonation may provide improved predictions of sequential metabolism, drug-drug interactions, and liver toxicities within specific liver anatomical regions.