title: Efflux and uptake transporters involved in the disposition of bazedoxifene.
abstract: Bazedoxifene, a novel selective estrogen receptor modulator, has complex pharmacokinetics with rapid absorption, high metabolic clearance, low oral bioavailability (6.25 %) and a slow elimination phase. Our hypothesis is that drug uptake and efflux transporters may play an important role in its disposition. To adequately cover all aspects of bazedoxifene transport, several approaches were undertaken: PAMPA assay, ATPase assay, membrane inside-out vesicles and Caco-2 and CHO cell lines. The results obtained from PAMPA experiments showed moderate passive permeability of bazedoxifene (P app ≈ 2 × 10(-6)cm/s), suggesting the existence of an active transport during the rapid absorption phase. The Caco-2 transport assay showed large and significant changes in the measured efflux ratios of bazedoxifene when selective transporter inhibitors were applied: verapamil (a Pgp inhibitor), MK571 (an MRP inhibitor), Ko143 (a BCRP inhibitor) and DIDS (an OATP inhibitor). Additionally, membrane preparation experiments demonstrated the interaction of bazedoxifene with P-gp, MRP2 and BCRP. CHO experiments did not show any interactions of bazedoxifene with OATP1B1 or OATP1B3; therefore, bazedoxifene may be a substrate of other OATP isoform(s). The comprehensive in vitro study indicates a strong involvement of Pgp, MRP, BCRP and OATP in bazedoxifene disposition.
authors: Department of Biopharmacy and Pharmacokinetics, Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, 1000, Ljubljana, Slovenia.
authors: Tina Trdan
authors: TT
authors: Lušin
authors: Department of Biopharmacy and Pharmacokinetics, Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, 1000, Ljubljana, Slovenia.
authors: Aleš
authors: A
authors: Mrhar
authors: Department of Clinical Pharmacology and Toxicology, University Hospital, Ramistrasse 100, 8091, Zurich, Switzerland.
authors: Bruno
authors: B
authors: Stieger
authors: Department of Biopharmacy and Pharmacokinetics, Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, 1000, Ljubljana, Slovenia.
authors: Albin
authors: A
authors: Kristl
authors: Lek d.d., Verovškova 57, 1000, Ljubljana, Slovenia.
authors: Katja
authors: K
authors: Berginc
authors: Department of Biopharmacy and Pharmacokinetics, Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, 1000, Ljubljana, Slovenia. jurij.trontelj@ffa.uni-lj.si.
authors: Jurij
authors: J
authors: Trontelj
mesh_terms: D017878:4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid / Q000378:metabolism; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2 / Q000378:metabolism; D000818:Animals; D001693:Biological Transport, Active / Q000502:physiology; D016466:CHO Cells; D018938:Caco-2 Cells; D002460:Cell Line; D045744:Cell Line, Tumor; D003412:Cricetulus; D054659:Diketopiperazines / Q000378:metabolism; D006576:Heterocyclic Compounds, 4 or More Rings / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000378:metabolism*; D027381:Liver-Specific Organic Anion Transporter 1 / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000378:metabolism*; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism; D029362:Organic Anion Transporters, Sodium-Independent / Q000378:metabolism; D010539:Permeability; D011422:Propionates / Q000378:metabolism; D011804:Quinolines / Q000378:metabolism; D014700:Verapamil / Q000378:metabolism
chemical_list: D017878:4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D054659:Diketopiperazines; D006576:Heterocyclic Compounds, 4 or More Rings; D007211:Indoles; D027381:Liver-Specific Organic Anion Transporter 1; D026901:Membrane Transport Proteins; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D029362:Organic Anion Transporters, Sodium-Independent; D011422:Propionates; D011804:Quinolines; D014700:Verapamil; C541506:3-(6-isobutyl-9-methoxy-1,4-dioxo-1,2,3,4,6,7,12,12a-octahydropyrazino(1',2'-1,6)pyrido(3,4-b)indol-3-yl)propionic acid tert-butyl ester; C059141:verlukast; C447119:bazedoxifene
keywords: Bazedoxifene; Efflux transporters; Uptake transporters
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