Abstract:
:The brain uptake index (BUI) method of Oldendorf was used to examine blood-brain barrier (BBB) drug transport in mice, rats, and rabbits; felbamate (FBM) extraction (E) in a single transcapillary passage was 5-20%, and drug uptake in rat brain was not concentration-dependent. Like diazepam, FBM was retained in mouse brain. To ensure that radioactivity measurements reflected the disposition of parent drug and not some metabolite, extracts of mouse brain were prepared for further analysis. No FBM metabolites were detected in brain 5 min after administration: In silica gel thin-layer chromatography (TLC), a single [14C]FBM peak was detected--Rf = 0.504 (70:30 acetone:hexane). Confirmatory high-performance liquid chromatography (HPLC) separations [30% methanol, 1.3 ml/min, C18 column, ultraviolet (UV) detection 254 nm] indicated a single peak containing greater than 93% of the radioactivity in the FBM fraction (12-min retention time). In a single transit through the liver (a nonbarrier tissue with fenestrated capillaries), FBM E was 82%. The octanol:buffered saline partition coefficient of FBM was (log PFBM =) 0.54 +/- 0.01. Thus, lipid-mediated BBB penetration of FBM is similar to that of phenytoin (PHT) and phenobarbital (PB). Plasma proteins do not affect FBM entry to the brain: neither human serum, nor bovine or human serum albumin (BSA, HSA), nor human alpha 1 acid glycoprotein (orosomucoid) significantly modified BBB FBM extraction. Erythrocyte-borne FBM may also dissociate and gain access to the brain in a single transcapillary passage. Differences between newborn and adult rabbit BBB FBM extraction and between different anesthetic agents are attributable to cerebral blood flow (CBF) rates. The permeability-surface area products (PS = [CBF].[E]) for FBM in rats, rabbits, and mice were 0.09, 0.16 and 0.30 ml/min/g, respectively. Preliminary autoradiographic analyses of frozen brain sections suggest that [14C]FBM distributes relatively uniformly throughout the brain and that minor variations apparently are a function of differing CBF rates.
journal_name
Epilepsiajournal_title
Epilepsiaauthors
Cornford EM,Young D,Paxton JW,Sofia RDdoi
10.1111/j.1528-1157.1992.tb02205.xsubject
Has Abstractpub_date
1992-09-01 00:00:00pages
944-54issue
5eissn
0013-9580issn
1528-1167journal_volume
33pub_type
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