Investigation of the distribution of EAB 515 to cortical ECF and CSF in freely moving rats utilizing microdialysis.
A freely moving rat model was developed to study the CNS distribution of EAB 515 (S-alpha-amino-5-phosphonomethyl[1,1'-biphenyl]-3-propanoic acid). Microdialysis (MD) in the frontal cortex (FrC) and in the lateral ventricle (LV) of the rat brain was performed to measure the levels of EAB 515 in the cortical extracellular fluid (ECF) as well as in the cerebrospinal fluid (CSF). The femoral artery and femoral vein were cannulated for serial blood sampling and intravenous (i.v.) drug administration, respectively. EAB 515 was also administered via the intracerebroventricular (icv) route in a cross-over experiment. The in vivo recovery of EAB 515 across the MD probes was determined by simultaneous retrodialysis (RD) performed using a hydroxylated analog of EAB 515, as the RD calibrator (RDC). An extremely sensitive and selective on-line HPLC system with native fluorescence detection was developed for the simultaneous analysis of EAB 515 and RDC in microdialysate samples from rat CSF and cortical ECF. Unbound concentrations of EAB 515 in the rat plasma were determined by direct injection of plasma ultrafiltrate onto the HPLC column. The validity of the use of RDC as the RD calibrator was demonstrated by comparing the results of zero-net flux (ZNF) analysis simultaneously in some experiments. After constant rate i.v. infusion in rats (n = 12) for 900 min, the average (S.D.) ratio of the levels of EAB 515 in the CSF to those in plasma (Ccsf.iv/Cp) was determined to be 17.7 (7.8)% and that in the cortex relative to plasma (Ccortex.iv/Cp) was 8.3 (4.8)%.(ABSTRACT TRUNCATED AT 250 WORDS)
Malhotra
B K
BK
Department of Pharmaceutics, College of Pharmacy, University of Minnesota, Minneapolis 55455.
Lemaire
M
M
Sawchuk
R J
RJ
D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D001713:Biphenyl Compounds / Q000493:pharmacokinetics*; D002540:Cerebral Cortex / Q000378:metabolism*; D005110:Extracellular Space / Q000378:metabolism*; D008297:Male; D008657:Metabolic Clearance Rate; D017551:Microdialysis; D016202:N-Methylaspartate / Q000037:antagonists & inhibitors*; D011339:Probenecid / Q000494:pharmacology; D011422:Propionates / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley
D001713:Biphenyl Compounds; D011422:Propionates; C077642:2-amino-5-phosphonomethyl(1,1'-biphenyl)-3-propanoic acid; D016202:N-Methylaspartate; D011339:Probenecid