title: Targeted brain delivery of 17 beta-estradiol via nasally administered water soluble prodrugs.
abstract: The utility of the nasal route for the systemic delivery of 17beta-estradiol was studied using watersoluble prodrugs of 17beta-estradiol. This delivery method was examined to determine if it will result in preferential delivery to the brain. Several alkyl prodrugs of 17beta-estradiol were prepared and their physicochemical properties were determined. In vitro hydrolysis rate constants in buffer, rat plasma, and rat brain homogenate were determined by high-performance liquid chromatography. In vivo nasal experiments were carried out on rats. Levels of 17beta-estradiol in plasma and cerebral spinal fluid (CSF) were determined with radioimunoassay using a gamma counter. The study revealed that the aqueous solubilities of the prodrugs were several orders of magnitude greater than 17beta-estradiol with relatively fast in vitro conversion in rat plasma. Absorption was fast following nasal delivery of the prodrugs with high bioavailability. CSF 17beta-estradiol concentration was higher following nasal delivery of the prodrugs compared to an equivalent intravenous dose. It was determined that water-soluble prodrugs of 17beta-estradiol can be administered nasally. These prodrugs are capable of producing high levels of estradiol in the CSF and as a result may have a significant value in the treatment of Alzheimer's disease.
authors.affiliation: Division of Pharmaceutical Sciences, University of Kentucky, Lexington, Kentucky 40536, USA.
authors.forename: Abeer M
authors.initials: AM
authors.lastname: Al-Ghananeem
authors.forename: Ashraf A
authors.initials: AA
authors.lastname: Traboulsi
authors.forename: Lewis W
authors.initials: LW
authors.lastname: Dittert
authors.forename: Anwar A
authors.initials: AA
authors.lastname: Hussain
mesh_terms: D000281:Administration, Intranasal; D000818:Animals; D001798:Blood Proteins / Q000378:metabolism; D001921:Brain / Q000201:enzymology / Q000378:metabolism; D001923:Brain Chemistry; D016503:Drug Delivery Systems; D004353:Drug Evaluation, Preclinical; D004951:Esterification; D004958:Estradiol / Q000008:administration & dosage* / Q000134:cerebrospinal fluid / Q000737:chemistry* / Q000493:pharmacokinetics; D006868:Hydrolysis; D008297:Male; D011355:Prodrugs / Q000008:administration & dosage* / Q000737:chemistry* / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility; D014867:Water / Q000737:chemistry*
chemical_list: D001798:Blood Proteins; D011355:Prodrugs; D014867:Water; D004958:Estradiol