Prediction of the intestinal first-pass metabolism of CYP3A and UGT substrates in humans from in vitro data

Abstract

  This study aimed to establish a practical and simplified method of predicting intestinal availability in humans (F_g,human) at the drug discovery stage using in vitro metabolic clearance values and permeability clearance values. A prediction model for F_g,human of 19 CYP3A substrates and 5 UGT substrates was constructed based on a concept considering that the permeability clearance values mean the permeability across the basal membrane with pH 7.4 on both sides. Permeability clearance values were obtained by PAMPA at pH 7.4. PAMPA is widely used in the pharmaceutical industry as the earliest primary screening and enables estimation of the kinetics of transport by passive diffusion. For CYP3A substrates, the metabolic clearance was obtained from in vitro intrinsic clearance values in human intestinal or hepatic microsomes (CL_int,HIM and CL_int,HLM, respectively). Using metabolic clearances corrected by the ratio of CL_int,HIM to CL_int,HLM, HLM showed equivalent predictability with HIM for CYP3A substrates. For UGT substrates, the clearance was obtained from those in alamethicin-activated HIM using one incubation with both NADPH and UDPGA cofactors. The method in this study could predict F_g,human for the compounds investigated, and represents a simplified method applicable to lower permeability compounds based on a new concept.