RT Journal Article
SR Electronic
T1 THE SYSTEMIC EXPOSURE OF AN <em>N-</em>METHYL-<span class="sc">d</span>-ASPARTATE RECEPTOR ANTAGONIST IS LIMITED IN MICE BY THE P-GLYCOPROTEIN AND BREAST CANCER RESISTANCE PROTEIN EFFLUX TRANSPORTERS
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 722
OP 726
DO 10.1124/dmd.32.7.722
VO 32
IS 7
A1 Joseph W. Polli
A1 Todd M. Baughman
A1 Joan E. Humphreys
A1 Kelly H. Jordan
A1 Angela L. Mote
A1 Lindsey O. Webster
A1 Robert J. Barnaby
A1 Giovanni Vitulli
A1 Luigina Bertolotti
A1 Kevin D. Read
A1 Cosette J. Serabjit-Singh
YR 2004
UL http://dmd.aspetjournals.org/content/32/7/722.abstract
AB 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 (&lt;10%) and plasma clearance (∼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 (Papp = 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. Cmax values changed in parallel with the AUC(0→6 h) values; however, tmax 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. The American Society for Pharmacology and Experimental Therapeutics