Influence of hepatic and intestinal efflux transporters and their genetic variants on the pharmacokinetics and pharmacodynamics of raloxifene in osteoporosis treatment.
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| Abstract |
Raloxifene exhibits a large and unexplained interindividual variability in its pharmacokinetics and pharmacodynamics. The aim of our study was to identify transporters involved in the efflux of raloxifene and its glucuronide metabolites by various in vitro models and by an in vivo study to explore the possible involvement of P-glycoprotein (Pgp), multidrug resistance-associated protein (MRP)1, MRP2, MRP3, and breast cancer resistance protein in the observed high interindividual variability. Experiments with the parallel artificial membrane permeability assay showed the highest passive permeability for raloxifene, followed by raloxifene-6-β-glucuronide (M1), raloxifene-4'-β-glucuronide (M2), and raloxifene-6,4'-diglucuronide (M3). Caco-2 cell monolayer experiments indicated an interaction of raloxifene with Pgp. The ATPase assay confirmed the raloxifene interaction with Pgp and indicated interactions of all raloxifene species with MRP1, MRP2, MRP3, and breast cancer resistance protein, except for M1, which did not show any interactions with MRP2. Furthermore, the vesicular experiments confirmed the interaction of M2 and M3 with MRP2. Although the in vivo study on osteoporotic postmenopausal women on raloxifene could not confirm a significant influence of ABCB1 and ABCC2 genetic polymorphisms on its pharmacokinetics, a clear trend toward higher total raloxifene concentrations was observed in carriers of at least 1 ABCB1 c.3435T allele. Moreover, the same polymorphism effect was also observed as a significant increase in total hip bone mineral density after 1 year of treatment. The results of our study support the involvement of efflux transporters in disposition of raloxifene and its metabolites and may partially explain the observed raloxifene variability by the influence of the ABCB1 c.3435C>T polymorphism.
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| Authors | Tina Trdan Lušin, Aleš Mrhar, Bruno Stieger, Gerd A Kullak-Ublick, Janja Marc, Barbara Ostanek, Andrej Zavratnik, Albin Kristl, Katja Berginc, Katja Delić, Jurij Trontelj |
| Journal | Translational research : the journal of laboratory and clinical medicine (Transl Res) Vol. 160 Issue 4 Pg. 298-308 (Oct 2012) ISSN: 1878-1810 [Electronic] United States |
| PMID | 22683417 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't) |
| Copyright | Copyright © 2012 Mosby, Inc. All rights reserved. |
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