A redox-based chemical delivery system that enhances estradiol distribution to the brain: disposition studies in the rat.
The disposition of a chemical delivery system for estradiol (E2-CDS) which is based on a redox dihydropyridine-pyridinium salt conversion was investigated in rats. Tissue and plasma concentrations of E2-CDS and the oxidized metabolite (E2-Q+) were evaluated at times ranging from 1 to 14 days after intravenous administration of E2-CDS formulated as a modified cyclodextrin inclusion complex. While E2-CDS levels were below HPLC assay detection limits for all samples by 1 day postdosing, E2-Q+ was readily quantified. The calculated half-life of E2-Q+ was longest in brain tissue, significantly shorter in heart, lung, and kidney tissues, and shortest in plasma. There was a linear relationship between administered E2-CDS dose and oxidized metabolite measured in brain as well as in other tissues collected 24 hr after drug administration. Coadministration of high doses of a similarly oxidizable dihydropyridine, 1-methyl-1,4-dihydronicotinamide (NMN), in a dimethylsulfoxide (DMSO) vehicle decreased E2-Q+ measured in brain and other tissues without significantly affecting the relative patterns of distribution in these tissues. Brain tissue E2Q+ levels were not detected after dosing with the oxidized metabolite.
Estes
K S
KS
Center for Drug Design and Delivery, College of Pharmacy, University of Florida, Gainesville 32610.
Keuth
V
V
Dietzel
K
K
Brewster
M E
ME
Bodor
N S
NS
Derendorf
H
H
D000818:Animals; D001921:Brain / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D004958:Estradiol / Q000008:administration & dosage / Q000493:pharmacokinetics*; D007275:Injections, Intravenous; D008297:Male; D010084:Oxidation-Reduction; D051381:Rats; D011919:Rats, Inbred Strains; D014018:Tissue Distribution
D004958:Estradiol