Pharmacokinetic and tissue distribution study of [14C]fluasterone in male Beagle dogs following intravenous, oral and subcutaneous dosing routes.

The purpose of this work was to compare the pharmacokinetics (PK) and tissue distribution of [14C]fluasterone following intravenous (iv), subcutaneous (sc) and oral (po) administration in male Beagle dogs. The main goal of the investigation was to discover if non-oral routes would alter parameters observed in this study following the administration of [14C]fluasterone. The oral formulation had a lower bioavailability (47%) compared to the sc formulation (84%). Po and sc administration resulted in a similar t(max); however, the observed C(max) following sc dosing was less than half of that after oral dosing. The sc route had the greatest overall exposure (AUC(0-infinity)). Tissue distribution analysis 2 h post-intravenous dosing showed that connective tissue (adipose and bone), liver, and skeletal muscle accumulated relatively high levels of fluasterone. The majority of the dose was retained during the first 24 h. Elimination of [14C]fluasterone-derived radioactivity following intravenous dosing resulted in urine and feces containing 7.6% and 28%, respectively, of the total dose over the first 24 h. Elimination of [14C]fluasterone-derived radioactivity following subcutaneous dosing resulted in 4.6% in urine and 7.8% in feces of the total dose over the first 24 h. Following oral dosing, elimination resulted in 3.8% in urine and 36% in feces over the first 24h. In conclusion, the sc route of administration offers some advantages to po and iv due to the prolonged release and increased retention through 24 h.

Identification of [14C]fluasterone metabolites in urine and feces collected from dogs after subcutaneous and oral administration of [14C]fluasterone.

The objective of this research was the identification of the metabolic profile of fluasterone, a synthetic derivative of dehydroepiandrosterone, in dogs treated orally or subcutaneously with [4-(14)C]fluasterone. Separation and characterization techniques used to identify the principal metabolites of fluasterone in urine and feces included high-performance liquid chromatography (HPLC), liquid scintillation spectrometry, HPLC/tandem mass spectrometry, and NMR. In urine, the majority of the radioactivity was present as two components that had apparent molecular weights consistent with their tentative identification as monoglucuronide conjugates of 4alpha-hydroxy-16alpha-fluoro-5-androsten-17beta-ol and X(alpha or beta)-4alpha-dihydroxy-16alpha-fluoro-5-androsten-17beta-ol. The identification of the monoglucuronide conjugate of 4alpha-hydroxy-16alpha-fluoro-5-androsten-17beta-ol was also supported by NMR data. In support of this identification, these metabolites were cleaved with glucuronidase enzyme treatment, which gave rise to components with molecular weights again consistent with the aglycones of a monohydroxylated, 17-keto reduced (dihydroxy) fluasterone metabolite and a dihydroxylated, 17-keto reduced (trihydroxy) fluasterone metabolite. In feces, nonconjugated material predominated. The primary metabolites eliminated in feces were the two hydroxy fluasterone metabolites arising from 17-reduction (16alpha-fluoro-5-androsten-17beta-ol and 16alpha-fluoro-5-androsten-17alpha-ol) and 4alpha-hydroxy-16alpha-fluoro-5-androsten-17beta-ol that was present in urine in glucuronide form.

Clinical characteristics and pharmacokinetics of purified soy isoflavones: single-dose administration to healthy men.

BACKGROUND: Soy isoflavones are potential cancer chemoprevention treatments. OBJECTIVE: We conducted safety studies of purified unconjugated genistein, daidzein, and glycitein, and defined pharmacokinetic parameters for their absorption and metabolism. DESIGN: Thirty healthy men ingested a single dose of 1 of 2 isoflavone preparations purified from soy. The delivered doses of genistein (1, 2, 4, 8, or 16 mg/kg body wt) were higher than those previously administered to humans. Formulation A was composed of 90 +/- 5% genistein, 10% daidzein, and 1% glycitein. Formulation B was composed of 43% genistein, 21% daidzein, and 2% glycitein. RESULTS: We observed no clinically significant behavioral or physical changes after treatment. We observed elevations in lipoprotein lipase and hypophosphatemia that were possibly related to the treatment but that were associated with no clinical toxicity. Considerable quantities of isoflavones were excreted in urine as conjugates. The terminal elimination rate, elimination half-life, area under the curve, maximum plasma concentration, apparent systemic clearance, and volume of distribution were estimated for genistein and daidzein. The mean elimination half-lives with both formulations were 3.2 h for free genistein and 4.2 h for free daidzein. The mean pseudo half-lives were 9.2 h for total genistein and 8.2 h for total daidzein. CONCLUSIONS: Dietary supplements of purified unconjugated isoflavones administered to humans in single doses exceeding normal dietary intake manyfold resulted in minimal clinical toxicity. Genistein and daidzein (free and total) were rapidly cleared from plasma and excreted in urine.