Purpose: Drug elimination in the liver consists of uptake, metabolism, biliary excretion, and sinusoidal efflux from the hepatocytes to the blood. We aimed to establish an accurate prediction method for liver clearance in rats, considering these four elimination processes. In vitro assays were combined to achieve improved predictions.
Methods: In vitro clearances for uptake, metabolism, biliary excretion and sinusoidal efflux were determined for 13 selected compounds with various physicochemical and pharmacokinetic properties. Suspended hepatocytes, liver microsomes and sandwich-cultured hepatocytes were evaluated as in vitro models. Based on the individual processes, in vivo hepatic clearance was calculated. Subsequently, the predicted clearances were compared with the corresponding in vivo values from literature.
Results: Using this in vitro-in vivo extrapolation method good linear correlation was observed between predicted and reported clearances. Linear regression analysis revealed much improved prediction for the novel method (r(2) = 0.928) as compared to parameter analysis using hepatocyte uptake only (r(2) = 0.600), microsomal metabolism only (r(2) = 0.687) or overall hepatobiliary excretion in sandwich-cultured hepatocytes (r(2) = 0.321).
Conclusions: In this new attempt to predict hepatic elimination under consideration of multiple clearance processes, in vivo hepatic clearances of 13 compounds in rats were well predicted using an IVIVE analysis method based on in vitro assays.