PT - JOURNAL ARTICLE AU - Keitaro Kadono AU - Takafumi Akabane AU - Kenji Tabata AU - Katsuhiko Gato AU - Shigeyuki Terashita AU - Toshio Teramura TI - Quantitative Prediction of Intestinal Metabolism in Humans from a Simplified Intestinal Availability Model and Empirical Scaling Factor AID - 10.1124/dmd.109.029322 DP - 2010 Jul 01 TA - Drug Metabolism and Disposition PG - 1230--1237 VI - 38 IP - 7 4099 - http://dmd.aspetjournals.org/content/38/7/1230.short 4100 - http://dmd.aspetjournals.org/content/38/7/1230.full SO - Drug Metab Dispos2010 Jul 01; 38 AB - This study aimed to establish a practical and convenient method of predicting intestinal availability (Fg) in humans for highly permeable compounds at the drug discovery stage, with a focus on CYP3A4-mediated metabolism. We constructed a “simplified Fg 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 (FaFg) values for these compounds were calculated from in vivo pharmacokinetic (PK) parameters, whereas in vitro intestinal intrinsic clearance (CLint,intestine) was determined using human intestinal microsomes. The CLint,intestine for the model compounds corrected with that of midazolam was defined as CLm,index and incorporated into a simplified Fg model with empirical scaling factor. Regardless of whether the compound was a P-gp substrate, the FaFg could be reasonably fitted by the simplified Fg model, and the value of the empirical scaling factor was well estimated. These results suggest that the effects of P-gp on Fa and Fg are substantially minor, at least in the case of highly permeable compounds. Furthermore, liver intrinsic clearance (CLint,liver) can be used as a surrogate index of intestinal metabolism based on the relationship between CLint,liver and CLm,index. Fg can be easily predicted using a simplified Fg model with the empirical scaling factor, enabling more confident selection of drug candidates with desirable PK profiles in humans. Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics