Impact of Intestinal Glucuronidation on the Pharmacokinetics of Raloxifene
| Autor: | Yuya Endo, Naomi Takeba, Keigo Kosaka, Minoru Tsuda-Tsukimoto, Toshiyuki Kume, Tomohiko Tanimoto, Norifumi Sakai, Masakatsu Takahashi, Ichiro Kino, Tatsuyuki Ohtsuka, Yuga Fukuhara |
|---|---|
| Rok vydání: | 2011 |
| Předmět: |
Male
medicine.medical_specialty Rats Gunn Glucuronidation Biological Availability Pharmaceutical Science Pharmacology Biochanin A Rats Sprague-Dawley chemistry.chemical_compound Dogs Glucuronides Pharmacokinetics Oral administration Microsomes Internal medicine Drug Discovery medicine Animals Gemfibrozil Raloxifene Glucuronosyltransferase Intestinal Mucosa Rats Wistar Multidrug Resistance-Associated Protein 2 Rats Bioavailability Macaca fascicularis Endocrinology Liver chemistry Raloxifene Hydrochloride Microsome Multidrug Resistance-Associated Proteins medicine.drug |
| Zdroj: | Drug Metabolism and Disposition. 39:1495-1502 |
| ISSN: | 1521-009X 0090-9556 |
| DOI: | 10.1124/dmd.111.040030 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|