title: 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).
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Chihiro
authors.initials: C
authors.lastname: Kondo
authors.forename: Reiko
authors.initials: R
authors.lastname: Onuki
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kusuhara
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Suzuki
authors.forename: Michiko
authors.initials: M
authors.lastname: Suzuki
authors.forename: Noriko
authors.initials: N
authors.lastname: Okudaira
authors.forename: Maho
authors.initials: M
authors.lastname: Kojima
authors.forename: Kazuya
authors.initials: K
authors.lastname: Ishiwata
authors.forename: Johan W
authors.initials: JW
authors.lastname: Jonker
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Sugiyama
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000577:Amides / Q000097:blood / Q000378:metabolism*; D000818:Animals; D001682:Biological Availability; D002460:Cell Line; D005260:Female; D007408:Intestinal Absorption; D007583:Jejunum / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D010477:Perfusion; D010880:Piperidines / Q000493:pharmacokinetics*; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors; D011355:Prodrugs / Q000493:pharmacokinetics*; D013876:Thiophenes / Q000493:pharmacokinetics*; D022161:Transport Vesicles / Q000378:metabolism
chemical_list: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; C501412:Abcg2 protein, mouse; D000577:Amides; C412309:ME 3229; C117060:ME 3277; D010880:Piperidines; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D011355:Prodrugs; D013876:Thiophenes