In vitro–in vivo extrapolation of metabolic clearance using human liver microsomes: factors showing variability and their normalization. (1st September 2020) - Morita, Keiichi
Abstract: In vitro – in vivo extrapolation (IVIVE) using human liver microsomes has been widely used to predict metabolic clearance, but some of the factors used in the process of prediction show variability for the same compound: notably, microsomal intrinsic clearance values corrected by the unbound fraction (CLint, u ), physiological parameters used for scale-up, and the source of in vivo clearance data. The purpose of this study was to assess the correlation between in vitro and in vivo CLint with a focus on factors showing variability using four cytochrome P450 (CYP)3A substrates. We surveyed in vivo clearance values in literature and also determined the microsomal CLint, u values. A scaling factor (SFdirect ) was defined as in vivo CLint divided by the microsomal CLint, u, which ranged from 1190 to 2310 (mg protein per kg body weight). The application of a mean SFdirect of 1600 (mg protein per kg body weight) and further normalization by the microsomal CLint, u values of midazolam, the most commonly used substrate, resulted in improved prediction accuracy for CLint, u values from various microsomal batches. The results suggest the normalization of variability might be useful for predicting the in vivo CLint .