The Role of Probenecid-Sensitive Organic Acid Transport in the Pharmacokinetics of N-Methyl-d-Aspartate Receptor Antagonists Acting at the GlycineB-Site: Microdialysis and Maximum Electroshock Seizures Studies

• Published in: The Journal of pharmacology and experimental therapeutics Vol. 290; no. 2; p. 543
• Main Authors: M. B. Hesselink, H. Smolders, B. Eilbacher, A. G. De Boer, D. D. Breimer, W. Danysz
• Format: Journal Article
• Language: English
• Published: American Society for Pharmacology and Experimental Therapeutics 01.08.1999
• ISSN: 0022-3565; 1521-0103

The purpose of the present study was to determine whether the probenecid-sensitive organic acid transporter is responsible for the short duration of action of a new group of N -methyl- d- aspartate receptor glycine B -site antagonists, MRZ 2/570, 2/571, and 2/576. A prolongation of their anticonvulsant activity from 60 to 180 to 240 min, was found in mice after pretreatment with probenecid (200 mg/kg i.p.). Microdialysis studies in rats showed that this is likely due to a change in central nervous system concentrations of these drugs because cotreatment with probenecid caused an increase in the brain extracellular fluid half-life (0.5- to 4-fold) and the brain area under the curve (1.8- to 3.6-fold). In serum the half-life of MRZ 2/576 (30 mg/kg) was also increased by coadministration of probenecid from 15.6 ± 1.3 to 40.6 ± 6.0 min. At steady state (MRZ 2/576, 20 mg/kg/h i.v.), brain extracellular fluid concentration was elevated 2.5-fold by concomitant administration of probenecid. These results clearly show that these glycine B -site antagonists are rapidly cleared from the systemic circulation and the central nervous system by the probenecid-sensitive organic acid transport system. Moreover, the present data show that MRZ 2/570, 2/571, and 2/576 reach the brain in concentrations (1.34–2.32 μM) above the range of their in vitro potencies at the glycine site of the N -methyl- d -aspartate receptor (0.1–1.0 μM).