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-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 microM) above the range of their in vitro potencies at the glycine site of the N-methyl-D-aspartate receptor (0.1-1.0 microM).
Department of Pharmacological Research, Merz + Co., Frankfurt/Main, Germany.
M B
MB
Hesselink
H
H
Smolders
B
B
Eilbacher
A G
AG
De Boer
D D
DD
Breimer
W
W
Danysz
D000818:Animals; D027321:Anion Transport Proteins; D001692:Biological Transport; D002352:Carrier Proteins / Q000378:metabolism*; D004347:Drug Interactions; D004597:Electroshock; D018691:Excitatory Amino Acid Antagonists / Q000493:pharmacokinetics*; D005260:Female; D008297:Male; D008559:Memantine / Q000494:pharmacology; D051379:Mice; D017551:Microdialysis; D010793:Phthalazines / Q000493:pharmacokinetics; D011339:Probenecid / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018009:Receptors, Glycine / Q000037:antagonists & inhibitors*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D012640:Seizures / Q000378:metabolism*
D027321:Anion Transport Proteins; D002352:Carrier Proteins; D018691:Excitatory Amino Acid Antagonists; C112266:MRZ 2-576; D010793:Phthalazines; D018009:Receptors, Glycine; D016194:Receptors, N-Methyl-D-Aspartate; D011339:Probenecid; D008559:Memantine