title: Quantitative prediction of intestinal glucuronidation of drugs in rats using in vitro metabolic clearance data.
abstract: UDP-glucuronosyltransferase (UGT) is highly expressed in the small intestine and catalyzes the glucuronidation of small molecules, which may affect the oral bioavailability of drugs. However, no method of predicting the in vivo observed fraction of absorbed drug (F(a)F(g)) affected by UGT has yet been established. Here, we investigated the relationship between F(a)F(g) and in vitro clearance of nine UGT substrates (ketoprofen, tolcapone, telmisartan, raloxifene, entacapone, resveratrol, buprenorphine, quercetin, and ezetimibe) via UGT in intestinal microsomes (CL(int, UGT)) in rats. F(a)F(g) was calculated from pharmacokinetic parameters after intravenous and oral administration or using the portal-systemic concentration difference method, with values ranging from 0.027 (ezetimibe) to 1 (tolcapone). Glucuronides of model compounds were observed in the portal plasma after oral administration, with CL(int, UGT) values ranging from 57.8 (tolcapone) to 19,200 µL/min/mg (resveratrol). An inverse correlation between F(a)F(g) and CL(int, UGT) was observed for most compounds and was described using a simplified intestinal availability model reported previously. This model gave accurate predictions of F(a)F(g) values for three in-house compounds. Our results show that F(a)F(g) in rats is affected by UGT and can be predicted using CL(int, UGT). This work should hasten the development of a method to predict F(a)F(g) in humans.
authors.affiliation: Analysis and Pharmacokinetics Research Laboratories, Astellas Pharma Inc., Tsukuba. takako-furukawa@jp.astellas.com
authors.forename: Takako
authors.initials: T
authors.lastname: Furukawa
authors.forename: Fumihiro
authors.initials: F
authors.lastname: Nakamori
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Tetsuka
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Naritomi
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Moriguchi
authors.forename: Katsuhiro
authors.initials: K
authors.lastname: Yamano
authors.forename: Shigeyuki
authors.initials: S
authors.lastname: Terashita
authors.forename: Toshio
authors.initials: T
authors.lastname: Teramura
mesh_terms: D000818:Animals; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005544:Forecasting; D020719:Glucuronides / Q000378:metabolism; D014453:Glucuronosyltransferase / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000378:metabolism*; D008297:Male; D008657:Metabolic Clearance Rate / Q000502:physiology; D008861:Microsomes / Q000378:metabolism; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D020719:Glucuronides; D004364:Pharmaceutical Preparations; D014453:Glucuronosyltransferase