title: The transnasal delivery of 5-fluorouracil to the rat brain is enhanced by acetazolamide (the inhibitor of the secretion of cerebrospinal fluid).
abstract: The purpose of the research is to evaluate the effect of acetazolamide (AZA), an inhibitor of the secretion of cerebrospinal fluid (CSF), on the direct drug transport from the nasal cavity to the CSF and the brain uptake of a model drug, 5-fluorouracil (5FU). 5FU was infused intravenously or perfused nasally in the presence and absence of intravenously administered AZA. Concentrations of 5FU in plasma, CSF and the cerebral cortex were measured. The AUC and the concentration of 5FU in the brain were used to calculate the apparent brain uptake clearance (CL(up)) of 5FU, which is an index of drug delivery to the brain under the two experimental conditions. Intravenous AZA markedly increased the concentration of 5FU in the CSF and brain following the nasal perfusion of 5FU, although the plasma concentrations of 5FU were similar with intravenous infusion and nasal perfusions of 5FU. CL(up) of 5FU after the nasal perfusion with AZA was significantly increased by 104% and 46% as compared to intravenous infusion and nasal perfusion without AZA, respectively. AZA enhanced the 5FU delivery to the brain through a nose-to-brain pathway by increasing the concentration of the nasally applied drug in the CSF.
authors.affiliation: Absorption Systems, 440 Creamery Way, Suite 300, Exton, PA 19341, USA. TShingaki@absorption.com
authors.forename: Tomotaka
authors.initials: T
authors.lastname: Shingaki
authors.forename: Ismael J
authors.initials: IJ
authors.lastname: Hidalgo
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Furubayashi
authors.forename: Hidemasa
authors.initials: H
authors.lastname: Katsumi
authors.forename: Toshiyasu
authors.initials: T
authors.lastname: Sakane
authors.forename: Akira
authors.initials: A
authors.lastname: Yamamoto
authors.forename: Shinji
authors.initials: S
authors.lastname: Yamashita
mesh_terms: D000086:Acetazolamide / Q000008:administration & dosage* / Q000494:pharmacology; D000281:Administration, Intranasal; D000818:Animals; D001921:Brain / Q000378:metabolism*; D002555:Cerebrospinal Fluid / Q000378:metabolism*; D004347:Drug Interactions; D005472:Fluorouracil / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D007262:Infusions, Intravenous; D008297:Male; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000086:Acetazolamide; D005472:Fluorouracil