TY - JOUR T1 - Quantitative Prediction of Human Intestinal Glucuronidation Effects on Intestinal Availability of UDP-Glucuronosyltransferase Substrates Using In Vitro Data JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 1771 LP - 1777 DO - 10.1124/dmd.112.045476 VL - 40 IS - 9 AU - Fumihiro Nakamori AU - Yoichi Naritomi AU - Ken-ichi Hosoya AU - Hiroyuki Moriguchi AU - Kazuhiro Tetsuka AU - Takako Furukawa AU - Keitaro Kadono AU - Katsuhiro Yamano AU - Shigeyuki Terashita AU - Toshio Teramura Y1 - 2012/09/01 UR - http://dmd.aspetjournals.org/content/40/9/1771.abstract N2 - We investigated whether the effects of intestinal glucuronidation on the first-pass effect can be predicted from in vitro data for UDP-glucuronosyltransferase (UGT) substrates. Human in vitro intrinsic glucuronidation clearance (CLint, UGT) for 11 UGT substrates was evaluated using pooled intestinal microsomes (4.00–4620 μl · min−1 · mg−1) and corrected by the free fraction in the microsomal mixture (CLuint, UGT = 5.2–5133 μl · min−1 · mg−1). Eleven UGT substrates were stable against intestinal cytochrome P450, indicating intestinal glucuronidation has a main effect on human intestinal availability. Oral absorbability intestinal availability (FaFg) values were calculated from in vivo pharmacokinetic parameters in the literature (FaFg = 0.01–1.0). It was found that CLuint, UGT and human FaFg have an inverse relationship that can be fitted to a simplified intestinal availability model. Experiments using Supersomes from insect cells expressing UGT isoforms showed that the substrates used were conjugated by various UGT isoforms. These results suggest that combining the simplified intestinal availability model and in vitro conjugation assay make it possible to predict human FaFg regardless of UGT isoform. ER -