Vol. 290, Issue 2, 543-550, August 1999

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

M. B. Hesselink^{1 2 3} , H. Smolders^{1 2} , B. Eilbacher, A. G. De Boer^{1 4}, D. D. Breimer^{1 4} and W. Danysz

Department of Pharmacological Research (M.B.H., H.S., B.E., W.D.), Merz + Co., Frankfurt/Main, Germany

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).