Abstract

This study aimed to establish a practical and convenient method of predicting intestinal availability (F_g) in humans for highly permeable compounds at the drug discovery stage, with a focus on CYP3A4-mediated metabolism. We constructed a “simplified F_g model,” described using only metabolic parameters, assuming that passive diffusion is dominant when permeability is high and that the effect of transporters in epithelial cells is negligible. Five substrates for CYP3A4 (alprazolam, amlodipine, clonazepam, midazolam, and nifedipine) and four for both CYP3A4 and P-glycoprotein (P-gp) (nicardipine, quinidine, tacrolimus, and verapamil) were used as model compounds. Observed fraction of drug absorbed (F_aF_g) values for these compounds were calculated from in vivo pharmacokinetic (PK) parameters, whereas in vitro intestinal intrinsic clearance (CL_{int,intestine}) was determined using human intestinal microsomes. The CL_{int,intestine} for the model compounds corrected with that of midazolam was defined as CL_m,index and incorporated into a simplified F_g model with empirical scaling factor. Regardless of whether the compound was a P-gp substrate, the F_aF_g could be reasonably fitted by the simplified F_g model, and the value of the empirical scaling factor was well estimated. These results suggest that the effects of P-gp on F_a and F_g are substantially minor, at least in the case of highly permeable compounds. Furthermore, liver intrinsic clearance (CL_int,liver) can be used as a surrogate index of intestinal metabolism based on the relationship between CL_int,liver and CL_m,index. F_g can be easily predicted using a simplified F_g model with the empirical scaling factor, enabling more confident selection of drug candidates with desirable PK profiles in humans.