Abstract
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 ofN-methyl-d-aspartate receptor glycineB-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 glycineB-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 theN-methyl-d-aspartate receptor (0.1–1.0 μM).
Footnotes
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Send reprint requests to: Dr. Wojciech Danysz, Merz + Co., Dept. of Pharmacological Research, Eckenheimer Landstrasse 100–104; 60318 Frankfurt/Main, Germany. E-mail:wojciech.danysz{at}merz.de
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↵1 Current address: Department of Pharmacology, Leiden/Amsterdam Center for Drug Research, Einsteinweg 55, 2300 RA Leiden, the Netherlands.
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↵2 On leave from Department of Pharmacology, Leiden/Amsterdam Center for Drug Research, Einsteinweg 55, 2300 RA Leiden, the Netherlands.
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↵3 Present address: Department of Neuropharmacology, Cerebrus Ltd., Oakdene Court, 613 Reading Road, Winnersh, Wokingham, RG41 5UA, UK.
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↵4 Present address: Department of Pharmacology, Leiden/Amsterdam Center for Drug Research, Einsteinweg 55, 2300 RA Leiden, the Netherlands.
- Abbreviations:
- NMDA
- N-methyl-d-aspartate
- CNS
- central nervous system
- ECF
- extracellular fluid
- AUC
- area under the curve
- glycineB-site
- strychnine-insensitive glycine coagonist site
- BBB
- blood-brain barrier
- MES
- maximal electroshock
- aCSF
- artificial cerebrospinal fluid
- PNQX
- pyrido[3,4-f]quinoxaline-2,3-dione,1,4,7,8,9,10-hexahydro-9-methyl-6-nitromethanesulfonate
- Received October 7, 1998.
- Accepted April 23, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
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