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Lack of Improvement of Oral Absorption of ME3277 by Prodrug Formation Is Ascribed to the Intestinal Efflux Mediated by Breast Cancer Resistant Protein (BCRP/ABCG2)

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Purpose.

ME3229, an ester-type prodrug of a hydrophilic glycoprotein IIb/IIIa antagonist (ME3277), failed to show improved oral absorption. Okudaira et al. (J. Pharmacol. Exp. Ther. 294. 580–587, 2000) provided a piece of evidence that this is ascribed to an efflux system, distinct from P-gp and MRP2, that extrudes ME3277 formed from ME3229 in the intestinal epithelial cells. The aim of the present study is to examine the involvement of breast cancer resistant protein (BCRP/ABCG2) as a cause of low oral absorption of ME3229.

Methods.

The transport activity of ME3277 in the presence and absence of ATP was determined using a rapid filtration method with the membrane vesicles prepared from LLC-PK1 cells expressing BCRP. The plasma concentrations of ME3229 and its metabolites were compared between Bcrp1−/− mice and wild-type mice after a single-pass perfusion of small intestine with ME3229.

Results.

The ATP-dependent uptake of ME3277 was greater in BCRP-expressing membrane vesicles than that in the control vesicles. Furthermore, it was found that after intestinal perfusion with ME3229 for 60 min, the plasma concentrations of ME3277 and PM-5, a metabolite of ME3229, increased 2-fold and 3-fold, respectively, in Bcrp1 knockout mice. It is possible that BCRP acts synergistically with intestinal carboxylesterases.

Conclusion.

These results suggest that Bcrp1 plays an important role in the intestinal efflux of ME3277 and, probably, PM-10 and PM-11, metabolites of ME3229, and limits its BA after oral administration of ME3229.

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Authors and Affiliations

  1. Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan

    Chihiro Kondo, Reiko Onuki, Hiroyuki Kusuhara, Michiko Suzuki & Yuichi Sugiyama

  2. Department of Pharmacy, The University of Tokyo Hospital, Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan

    Hiroshi Suzuki

  3. Pharmaceutical Research Center, Meiji Seika Kaisha, Ltd., Yokohama, 222-8567, Japan

    Noriko Okudaira, Maho Kojima & Kazuya Ishiwata

  4. Division of Experimental Therapy, The Netherlands Cancer Institute, 1066 CX, Amsterdam, The Netherlands

    Johan W. Jonker

Authors
  1. Chihiro Kondo
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  2. Reiko Onuki
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  3. Hiroyuki Kusuhara
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  4. Hiroshi Suzuki
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  5. Michiko Suzuki
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  6. Noriko Okudaira
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  7. Maho Kojima
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  8. Kazuya Ishiwata
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  9. Johan W. Jonker
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  10. Yuichi Sugiyama
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Correspondence to Yuichi Sugiyama.

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Kondo, C., Onuki, R., Kusuhara, H. et al. Lack of Improvement of Oral Absorption of ME3277 by Prodrug Formation Is Ascribed to the Intestinal Efflux Mediated by Breast Cancer Resistant Protein (BCRP/ABCG2). Pharm Res 22, 613–618 (2005). https://doi.org/10.1007/s11095-005-2487-9

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  • DOI: https://doi.org/10.1007/s11095-005-2487-9

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