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.

This article is available online at http://dmd.aspetjournals.org ABSTRACT: GV196771 (E-4,6-dichloro-3-(2-oxo-1-phenyl-pyrrolidin-3-glyden- emethyl)-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 clear- ance (2 ml/min/kg) in rats. P-Glycoprotein (Pgp) and breast can- cer 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 involve- ment 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 (B3A/A3B) ratio 5.1) with high pas- sive membrane permeability (Papp 64-170 nm/s); however, GV196771 was not an in vitro Mdr1a substrate (B3A/A3B 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 pretreat- ment 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 (03 6h ) ) 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(03 6h )values; however, tmax remained relatively un- changed. This study supports a role for Pgp and Bcrp in attenuat- ing 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.