Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)

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Kondo, C. 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).

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.[1]

References

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). Kondo, C., Onuki, R., Kusuhara, H., Suzuki, H., Suzuki, M., Okudaira, N., Kojima, M., Ishiwata, K., Jonker, J.W., Sugiyama, Y. Pharm. Res. (2005) [Pubmed]

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