Dose and Time-Course Evaluation of a Redox-Based Estradiol-Chemical Delivery System for the Brain. I. Tissue Distribution

Brain-enhanced delivery and sustained release of estradiol (E₂) may be potentially useful in the treatments of vasomotor hot flushes and prostatic adenocarcinoma and for fertility regulation. Therefore, we have evaluated a redox-based estradiol-chemical delivery system (E₂-CDS) for the brain. The mechanism of this drug delivery is based on an interconvertible dihydropyridine⇌pyridinium salt redox reaction. In this study, we investigated the dose- and time-dependent effects of E₂-CDS on the tissue distribution of E₂-Q⁺ and E₂, the inactive (intermediate) and active metabolites, respectively, of the E₂-CDS. Ovariectomized rats received a single iv injection of E₂-CDS at 0.01, 0.1, or 1.0 mg/kg or an E₂ dose of 0.7 mg/kg or the drug's vehicle, 2-hydroxypropyl-β-cyclodextrin (HPCD), on day 0. Tissue samples including brain and peripheral tissues were then analyzed for both E₂-Q⁺ and E₂ at 1, 7, 14, 21, or 28 days following the E₂-CDS administration. Initially, both E₂-Q⁺ and E₂ were detected in all tissues analyzed. The dose-distribution and time-course study demonstrates that (1) at 24 hr (1 day) after administration of E₂-CDS, all tissues showed a dose-proportional increase in concentrations of E₂-Q⁺ and E₂; (2) the enzymatic oxidation of E₂-CDS to E₂-Q⁺ was dose dependent over the 100-fold dose range examined; and (3) the disappearance of E₂-Q⁺ as well as E₂ was slow in whole brain and hypothalamus, with an apparent t\(\frac{1}{2}\) = 8–9 days, while both of these metabolites were rapidly cleared from plasma, liver, fat, anterior pituitary, kidney, lung, heart, and uterus. Finally, when the kinetic behaviors of E₂-CDS and E₂ were compared on molar basis, the E₂-CDS (1.0-mg/kg dose) produced E₂ concentrations in brain tissue which were 81- and 182-fold greater than those achieved following equimolar E₂ (0.7 mg/kg) injection at 1 and 7 days, respectively. These data demonstrate that the E₂-CDS is much more effective than E₂ itself in delivering the estrogen to the brain. Collectively, these data support the concept of the brain-enhanced delivery and sustained release of E₂ using the redox-based chemical delivery system.