Abstract

Intestinal first-pass metabolism may contribute to low oral drug bioavailability and drug-drug interactions, particularly for CYP3A substrates. The current analysis predicted intestinal availability (F_G) from in vitro metabolic clearance and permeability data of 25 drugs using the Q_Gut model. The drug selection included a wide range of physicochemical properties and in vivo F_G values (0.07–0.94). In vitro clearance data (CLu_int) were determined in human intestinal (HIM) and three liver (HLM) microsomal pools (n = 105 donors) using the substrate depletion method. Apparent drug permeability (P_app) was determined in Caco-2 and Madin-Darby canine kidney cells transfected with human MDR1 gene (MDCK-MDR1 cells) under isotonic conditions (pH = 7.4). In addition, effective permeability (P_eff) data, estimated from regression analyses to P_app or physicochemical properties were used in the F_G predictions. Determined CLu_int values ranged from 0.022 to 76.7 μl/min/pmol of CYP3A (zolpidem and nisoldipine, respectively). Differences in CLu_int values obtained in HIM and HLM were not significant after normalization for tissue-specific CYP3A abundance, supporting their interchangeable usability. The F_G predictions were most successful when P_app data from Caco-2/MDCK-MDR1 cells were used directly; in contrast, the use of physicochemical parameters resulted in significant F_G underpredictions. Good agreement between predicted and in vivo F_G was noted for drugs with low to medium intestinal extraction (e.g., midazolam predicted F_G value 0.54 and in vivo value 0.51). In contrast, low prediction accuracy was observed for drugs with in vivo F_G <0.5, resulting in considerable underprediction in some instances, as for saquinavir (predicted F_G is 6% of the observed value). Implications of the findings are discussed.