Lušin Tina Trdan, Mrhar Aleš, Stieger Bruno, Kristl Albin, Berginc Katja, Trontelj Jurij
Department of Biopharmacy and Pharmacokinetics, Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, 1000, Ljubljana, Slovenia.
Department of Clinical Pharmacology and Toxicology, University Hospital, Ramistrasse 100, 8091, Zurich, Switzerland.
Eur J Drug Metab Pharmacokinet. 2016 Jun;41(3):251-7. doi: 10.1007/s13318-015-0256-7. Epub 2015 Jan 29.
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.
巴泽多昔芬是一种新型选择性雌激素受体调节剂，其药代动力学较为复杂，具有吸收迅速、代谢清除率高、口服生物利用度低（6.25%）以及消除相缓慢的特点。我们的假设是药物摄取和外排转运体可能在其处置过程中发挥重要作用。为了全面涵盖巴泽多昔芬转运的各个方面，我们采用了多种方法：平行人工膜渗透试验（PAMPA）、ATP酶试验、内翻膜囊泡以及Caco-2和CHO细胞系。PAMPA实验结果显示巴泽多昔芬具有适度的被动通透性（表观渗透系数P app≈2×10⁻⁶cm/s），这表明在快速吸收阶段存在主动转运。当应用选择性转运体抑制剂时，Caco-2转运试验显示巴泽多昔芬的外排比率发生了巨大且显著的变化：维拉帕米（一种P-糖蛋白抑制剂）、MK571（一种多药耐药相关蛋白抑制剂）、Ko143（一种乳腺癌耐药蛋白抑制剂）和DIDS（一种有机阴离子转运多肽抑制剂）。此外，膜制备实验证明了巴泽多昔芬与P-糖蛋白、多药耐药相关蛋白2和乳腺癌耐药蛋白之间的相互作用。CHO实验未显示巴泽多昔芬与有机阴离子转运多肽1B1或有机阴离子转运多肽1B3之间存在任何相互作用；因此，巴泽多昔芬可能是其他有机阴离子转运多肽同工型的底物。这项全面的体外研究表明P-糖蛋白、多药耐药相关蛋白（MRP）、乳腺癌耐药蛋白（BCRP）和有机阴离子转运多肽（OATP）在巴泽多昔芬处置过程中发挥着重要作用。
