title: The systemic exposure of an N-methyl-D-aspartate receptor antagonist is limited in mice by the P-glycoprotein and breast cancer resistance protein efflux transporters.
abstract: GV196771 [E-4,6-dichloro-3-(2-oxo-1-phenyl-pyrrolidin-3-glydenemethyl)-1H-indole-2 carboxylic acid] is a potent antagonist of the modulatory glycine site of the N-methyl-d-aspartate receptor. GV196771 has low oral bioavailability (<10%) and plasma clearance ( approximately 2 ml/min/kg) in rats. P-Glycoprotein (Pgp) and breast cancer resistance protein (Bcrp) are ATP-binding cassette (ABC) transporters that limit the oral absorption of drugs and dietary constituents. The objective of this work was to assess the involvement of Pgp and/or Bcrp on the systemic exposure of GV196771 in mice. In vitro, GV196771 was a Bcrp substrate [basolateral-to-apical/apical-to-basolateral (B-->A/A-->B) ratio = 5.1] with high passive membrane permeability (P(app) = 64-170 nm/s); however, GV196771 was not an in vitro Mdr1a substrate (B-->A/A-->B ratio = 1.9; no effect of GF120918 on efflux ratio). The role of Pgp and Bcrp on the systemic exposure of GV196771 was assessed by pretreatment of wild-type and Pgp-deficient mdr1a/1b(-/-) mice with a single oral dose of GF120918 (50 mg/kg; a dual Pgp and Bcrp inhibitor) or vehicle (0.5% hydroxypropylmethylcellulose and 1% Tween 80) 2 h before administration of a single oral dose of GV196771 (2 mg/kg). Compared with wild-type animals, the GV196771 area under the plasma concentration-time curve [AUC((0-->6 h))] increased 6.2-fold in Pgp-deficient mice, 10.3-fold in GF120918-pretreated wild-type mice, and 16.4-fold in GF120918-pretreated Pgp-deficient mice. C(max) values changed in parallel with the AUC((0-->6 h)) values; however, t(max) remained relatively unchanged. This study supports a role for Pgp and Bcrp in attenuating the systemic exposure of GV196771 in mice and demonstrates that two ABC efflux transporters can have nonredundant roles in attenuating the disposition of a compound.
authors.affiliation: GlaxoSmithKline, Inc., P.O. Box 13398, Room: MAI.A2213, Research Triangle Park, NC 27709, USA. joseph.w.polli@gsk.com
authors.forename: Joseph W
authors.initials: JW
authors.lastname: Polli
authors.forename: Todd M
authors.initials: TM
authors.lastname: Baughman
authors.forename: Joan E
authors.initials: JE
authors.lastname: Humphreys
authors.forename: Kelly H
authors.initials: KH
authors.lastname: Jordan
authors.forename: Angela L
authors.initials: AL
authors.lastname: Mote
authors.forename: Lindsey O
authors.initials: LO
authors.lastname: Webster
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Barnaby
authors.forename: Giovanni
authors.initials: G
authors.lastname: Vitulli
authors.forename: Luigina
authors.initials: L
authors.lastname: Bertolotti
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Read
authors.forename: Cosette J
authors.initials: CJ
authors.lastname: Serabjit-Singh
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000172:deficiency / Q000378:metabolism*; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000166:Acridines / Q000494:pharmacology; D000818:Animals; D002219:Carbamates; D002460:Cell Line; D002853:Chromatography, Liquid; D005663:Furans; D007211:Indoles / Q000493:pharmacokinetics*; D008297:Male; D013058:Mass Spectrometry; D051379:Mice; D018345:Mice, Knockout; D011758:Pyrroles / Q000493:pharmacokinetics*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology; D044005:Tetrahydroisoquinolines / Q000494:pharmacology; D013997:Time Factors
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; C501412:Abcg2 protein, mouse; D000166:Acridines; D002219:Carbamates; D005663:Furans; C119836:GV 196771A; D007211:Indoles; D011758:Pyrroles; D016194:Receptors, N-Methyl-D-Aspartate; D013449:Sulfonamides; D044005:Tetrahydroisoquinolines; C095108:amprenavir; C083501:Elacridar