Three-dimensional quantitative structure activity relationship analyses of substrates for CYP2B6. J Pharmacol Exp Ther 288:21–29

Future alternatives to the presently accepted in vitro paradigm of prediction of intrinsic clearance, which could be used earlier in the drug discovery process, would potentially accelerate efforts to identify better drug candidates with more favorable metabolic profiles and less likelihood of failure with regard to human pharmacokinetic attributes. In this study we describe two computational methods for modeling human microsomal and hepatocyte intrinsic clearance data derived from our labo-ratory and the literature, which utilize pharmacophore features or descriptors derived from molecular structure. Human micro-somal intrinsic clearance data generated for 26 known thera-peutic drugs were used to build computational models using commercially available software (Catalyst and Cerius2), after first converting the data to hepatocyte intrinsic clearance. Th