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Efflux and uptake transporters involved in the disposition of bazedoxifene

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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 × 10−6cm/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.

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Abbreviations

ABC transporters:

ATP-binding cassette transporters

ABCB1:

ATP-binding cassette sub-family B member 1

BCRP:

Breast cancer resistance protein

BSEP:

Bile salt export pump

CHO:

Chinese hamster ovary

DIDS:

4,4′-Diisothiocyanatostilbene-2,2′-disulfonic acid

DMSO:

Dimethylsulfoxide

E17βG:

Estradiol-17β-glucuronide

E-3-S:

Estrone-3-sulfate

ER:

Efflux ratio

FA:

Formic acid

FLU:

Fluorescein

ICG:

Indocyanine green

LC-MS/MS:

Liquid chromatography-tandem mass spectrometry

MRP:

Multidrug resistance-associated protein

OATP:

Organic anion-transporting polypeptide

PAMPA:

Parallel artificial membrane permeability assay

Pgp:

P-glycoprotein

Pi:

Inorganic phosphate

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Acknowledgments

The authors are thankful to Assoc. Prof. Lucija Peterlin-Mašič for help with the chemical synthesis of bazedoxifene.

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Authors and Affiliations

  1. Department of Biopharmacy and Pharmacokinetics, Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, 1000, Ljubljana, Slovenia

    Tina Trdan Lušin, Aleš Mrhar, Albin Kristl & Jurij Trontelj

  2. Department of Clinical Pharmacology and Toxicology, University Hospital, Ramistrasse 100, 8091, Zurich, Switzerland

    Bruno Stieger

  3. Lek d.d., Verovškova 57, 1000, Ljubljana, Slovenia

    Katja Berginc

Authors
  1. Tina Trdan Lušin
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  2. Aleš Mrhar
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  3. Bruno Stieger
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  4. Albin Kristl
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  5. Katja Berginc
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  6. Jurij Trontelj
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Correspondence to Jurij Trontelj.

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Lušin, T.T., Mrhar, A., Stieger, B. et al. Efflux and uptake transporters involved in the disposition of bazedoxifene. Eur J Drug Metab Pharmacokinet 41, 251–257 (2016). https://doi.org/10.1007/s13318-015-0256-7

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  • DOI: https://doi.org/10.1007/s13318-015-0256-7

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