Efflux and uptake transporters involved in the disposition of bazedoxifene

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.