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Abstract

A redox-based chemical delivery system for estradiol (E2-CDS) has been shown capable of sustained and brain-selective delivery of estradiol (E2). A reversed-phase high-performance liquid chromatographic (HPLC) method is presented for the analysis of E2-CDS and its oxidized quaternary metabolite (E2-Quat) in biological fluids or tissues. The assay utilized a precolumn enrichment technique and detects plasma levels down to 10 ng/ml E2-Quat and 20 ng/ml E2-CDS. Sample preparation is rapid and simple. Samples are homogenized with acetonitrile, then centrifuged, and the supernatant is directly injected into the HPLC system. A water delivering pump injects the sample on a precolumn where the drug is concentrated. The mobile phase backflushes the retained compound onto the analytical column. At the same time, another sample can be injected onto a second precolumn. This alternating precolumn sample enrichment technique allows the injection of large volumes, up to 1800 microliters. Plasma and tissue samples of rats collected after i.v. administration of a single 15-mg/kg E2-CDS dose were analyzed for E2-CDS and E2-Quat by this procedure. The results show sustained brain levels of E2-Quat and prolonged half-life in brain compared to six peripheral tissues measured. These data support the concept of brain-targeted delivery using redox carrier systems of this type.

Targeting drugs to the brain by redox chemical delivery systems

“…In vitro experiments and distribution studies in rats showed a facile oxidation of 27 to 28 having a considerably longer t 1/2 in brain than that of those measured in peripheral tissues. 122,123 Pharmacokinetic studies in dogs revealed that 28 is rapidly eliminated from the periphery by both biliary and renal excretion, 124 but pharmacologically signi®cant amounts of it together with estradiol itself were measured in the CNS. 125 Pharmacological evaluation of the CDS in rats also con®rmed effects consistent with a long-lasting central estrogenization including decreased food intake, decreased body weight gain, libido enhancement, altered secretion of growth hormone and LH, and suppression of androgens and androgen-dependent tissues.…”

“All in the Mind”? Brain-Targeting Chemical Delivery System of 17β-Estradiol (Estredox) Produces Significant Uterotrophic Side Effect

“…The main human estrogen, 17β-estradiol (E2, Figure 1), has been undoubtedly the most studied compound to which the CDS approach has been applied [1,9,10,11,13,14], and is a typical example in this context. Although E2’s vast central effects [15,16] have allowed for the use of various in vivo experimental models for exploratory studies to observe attractive neuropharmacological responses, biopharmaceutical analyses focused specifically on E2 are still a formidable obstacle for the group pursuing the development of E2-CDS [9–11].…”

Amatoxins bearing amino and carboxyl groups prepared by selective alteration of the aldehyde generated by periodate oxidation of methylated α‐amanitin1

“…The solution was filtered, adjusted to 22% with respect to CH,CN, and subjected to HPLC with 22% CH,CN as the developing solvent. The periodate oxidation of meAMA in water has been found to yield two chemically similar forms of aldomeAMA which are apparently not free aldehydes and which interconvert in solution (6,9). The equilibrium mixture of these two forms will be referred to as aldomeAMA-IA/IB.…”

“…The total yield in this case was 18.8 pmol (92%). Yet another form of aldomeAMA which has properties of a free aldehyde can be isolated from periodate oxidation reactions performed in acidic solutions (6,9). This material will be designated aldomeAMA-11.…”

“…There appeared to be only a slow modification of the indole nucleus of the toxin as evidenced on TLC analysis by the appearance of components with altered reactivity to cinnamaldehyde/HCl. When meAMA was oxidized with periodate under acidic conditions, a form of aldomeAMA which appeared to be a free aldehyde was formed and could be isolated (9). This form of aldomeAMA (designated aldomeAMA-11) can be readily oxidized with NaC 10, to yield the corresponding carboxylic acid, meAMA-COOH.…”