PT - JOURNAL ARTICLE AU - Polli, Joseph W. AU - Baughman, Todd M. AU - Humphreys, Joan E. AU - Jordan, Kelly H. AU - Mote, Angela L. AU - Webster, Lindsey O. AU - Barnaby, Robert J. AU - Vitulli, Giovanni AU - Bertolotti, Luigina AU - Read, Kevin D. AU - Serabjit-Singh, Cosette J. TI - 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 AID - 10.1124/dmd.32.7.722 DP - 2004 Jul 01 TA - Drug Metabolism and Disposition PG - 722--726 VI - 32 IP - 7 4099 - http://dmd.aspetjournals.org/content/32/7/722.short 4100 - http://dmd.aspetjournals.org/content/32/7/722.full SO - Drug Metab Dispos2004 Jul 01; 32 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