Prediction of Human Intestinal First-Pass Metabolism of 25 CYP3A Substrates from In Vitro Clearance and Permeability Data

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 (CLuint) 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 Papp or physicochemical properties were used in the FG predictions. Determined CLuint values ranged from 0.022 to 76.7 mu l/min/pmol of CYP3A (zolpidem and nisoldipine, respectively). Differences in CLuint 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 Papp 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 FG was noted for drugs with low to medium intestinal extraction (e.g., midazolam predicted FG 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 FG is 6% of the observed value). Implications of the findings are discussed.