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 (∼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.
Footnotes
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ABBREVIATIONS: NMDA, N-methyl-d-aspartate; A→B, apical-to-basolateral; B→A, basolateral-to-apical; ABC, ATP-binding cassette; AUC, area under the plasma concentration-time curve; Bcrp, breast cancer resistance protein; Bcrp-MDCKII, Madin-Darby canine kidney cells transfected with the BCRP gene; CL, systemic plasma clearance; Cmax, maximum plasma concentration; GF120918, N-(4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)ethyl]-phenyl)-9,10-dihydro-5-methoxy-9-oxo-4-acridine carboxamide; GV150524, C20H13Cl2N2O3; GV196771, E-4,6-dichloro-3-(2-oxo-1-phenyl-pyrrolidin-3-glydenemethyl)-1H-indole-2 carboxylic acid; LC-MS/MS, high-performance liquid chromatography with tandem mass spectrometry; MB, mass balance; MDR, multidrug resistance; mdr1a-LLC-PK1, porcine kidney cells transfected with the mouse mdr1a gene; Papp, apparent permeability; Pgp, P-glycoprotein.
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↵1 Present address: Robert Barnaby, Dept of Drug Metabolism and Pharmacokinetics, Astra Zeneca, Alderley Park, Macclesfield, Cheshire SK104TG England
- Received January 30, 2004.
- Accepted April 5, 2004.
- The American Society for Pharmacology and Experimental Therapeutics
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