title: Impact of intestinal glucuronidation on the pharmacokinetics of raloxifene.
abstract: Raloxifene is extensively glucuronidated in humans, effectively reducing its oral bioavailability (2%). It was also reported to be glucuronidated in preclinical animals, but its effects on the oral bioavailability have not been fully elucidated. In the present study, raloxifene and its glucuronides in the portal and systemic blood were monitored in Gunn rats deficient in UDP-glucuronosyltransferase (UGT) 1A, Eisai hyperbilirubinemic rats (EHBRs), which hereditarily lack multidrug resistance-associated protein (MRP) 2, and wild-type rats after oral administration. The in vitro-in vivo correlation (IVIVC) of four UGT substrates (raloxifene, biochanin A, gemfibrozil, and mycophenolic acid) in rats was also evaluated. In Gunn rats, the product of fraction absorbed and intestinal availability and hepatic availability of raloxifene were 0.63 and 0.43, respectively; these values were twice those observed in wild-type Wistar rats, indicating that raloxifene was glucuronidated in both the liver and intestine. The ratio of glucuronides to unchanged drug in systemic blood was substantially higher in EHBRs (129-fold) than in the wild-type Sprague-Dawley rats (10-fold), suggesting the excretion of raloxifene glucuronides caused by MRP2. The IVIVC of the other UGT substrates in rats displayed a good relationship, but the oral clearance values of raloxifene and biochanin A, which were extensively glucuronidated by rat intestinal microsomes, were higher than the predicted clearances using rat liver microsomes, suggesting that intestinal metabolism may be a great contributor to the first-pass effect. Therefore, evaluation of intestinal and hepatic glucuronidation for new chemical entities is important to improve their pharmacokinetic profiles.
authors.affiliation: DMPK Research Laboratory, Mitsubishi Tanabe Corporation, 2-2-50, Kawagishi, Toda-shi, Saitama, 335-8505, Japan. kosaka.keigo@ma.mt-pharma.co.jp
authors.forename: Keigo
authors.initials: K
authors.lastname: Kosaka
authors.forename: Norifumi
authors.initials: N
authors.lastname: Sakai
authors.forename: Yuya
authors.initials: Y
authors.lastname: Endo
authors.forename: Yuga
authors.initials: Y
authors.lastname: Fukuhara
authors.forename: Minoru
authors.initials: M
authors.lastname: Tsuda-Tsukimoto
authors.forename: Tatsuyuki
authors.initials: T
authors.lastname: Ohtsuka
authors.forename: Ichiro
authors.initials: I
authors.lastname: Kino
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Tanimoto
authors.forename: Naomi
authors.initials: N
authors.lastname: Takeba
authors.forename: Masakatsu
authors.initials: M
authors.lastname: Takahashi
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Kume
mesh_terms: D000818:Animals; D001682:Biological Availability; D004285:Dogs; D055808:Drug Discovery / Q000379:methods; D020719:Glucuronides / Q000378:metabolism*; D014453:Glucuronosyltransferase / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D008252:Macaca fascicularis; D008297:Male; D008861:Microsomes / Q000378:metabolism; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism; D020849:Raloxifene Hydrochloride / Q000493:pharmacokinetics*; D051381:Rats; D011911:Rats, Gunn; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D000099148:UGT1A1 Enzyme
chemical_list: D020719:Glucuronides; D014453:Glucuronosyltransferase; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D020849:Raloxifene Hydrochloride; C000715087:ABCC2 protein, human; C499946:Ugt1a1 protein, rat; D000099148:UGT1A1 Enzyme