The role of probenecid-sensitive organic acid transport in the pharmacokinetics of N-methyl-D-aspartate receptor antagonists acting at the glycine(B)-site: Microdialysis and maximum electroshock seizures studies

The purpose of the present study was to determine whether the probenecid-se nsitive organic acid transporter is responsible for the short duration of a ction of a new group of N-methyl-D-aspartate receptor glycine(B)-site antag onists, 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 w ith 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 b rain extracellular fluid half-life (0.5- to 4-fold) and the brain area unde r 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 ex tracellular fluid concentration was elevated 2.5-fold by concomitant admini stration of probenecid. These results clearly show that these glycine(B)-si te antagonists are rapidly cleared from the systemic circulation and the ce ntral nervous system by the probenecid-sensitive organic acid transport sys tem. Moreover, the present data show that MRZ 2/570, 2/571, and 2/576 reach the brain in concentrations (1.34-2.32 mu M) above the range of their in v itro potencies at the glycine site of the N-methyl-D-aspartate receptor (0. 1-1.0 mu M).