ISSN:
1573-904X
Schlagwort(e):
chemical delivery system
;
blood–brain barrier
;
estradiol
;
tissue distribution
Quelle:
Springer Online Journal Archives 1860-2000
Thema:
Chemie und Pharmazie
Notizen:
Abstract 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.
Materialart:
Digitale Medien
URL:
http://dx.doi.org/10.1023/A:1015999318729
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