Center for Biomedical Research, The Population Council, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA.
Steroids. 2010 Mar;75(3):252-64. doi: 10.1016/j.steroids.2009.12.011. Epub 2010 Jan 11.
A synthetic progestin Nestorone is being developed for female-contraception. This study was conducted to determine the distribution, metabolism, and excretion of tritium-labeled Nestorone ((3)H Nestorone) in adult female rats. Rats were injected subcutaneously (S.C.) with a single dose of 400 microCi (3)H Nestorone/kg BW. Its distribution and concentrations in blood, plasma and other tissues were determined at defined times. The excreta were examined for elimination of (3)H Nestorone. Radioactivity in all samples was analyzed by liquid scintillation counter. Metabolite profiling was performed by HPLC and LC/MS analysis of the plasma, urine, and feces samples. Following subcutaneous injection of (3)H Nestorone, the mean peak concentrations of radioactivity (C(max)) in the blood and plasma were 58.1 and 95.5 ng equiv. (3)H Nestorone/g, respectively, at 2-h postdose (T(max)). Thereafter, the concentration of drug steadily declined through 96-h postdose with a terminal elimination half-life (t(1/2)) of 15.6 h. (3)H Nestorone-derived radioactivity was widely distributed in most tissues by 0.5 h and attained a mean maximal concentration by 2-h postdose. Approximately, 81.4% and 7.62% of the administered dose was excreted via feces and urine, respectively. In vivo metabolism of (3)H Nestorone resulted into a total of 19 metabolites. Among them, two metabolites viz., 17alpha-deacetyl-Nestorone (M9) and 4,5-dihydro-17alpha-deacetyl-Nestorone (M19) were identified by HPLC and LC/MS analysis. Metabolite profiling of plasma samples showed that most of the circulating radioactivity was associated with unchanged parent drug, and M19. The M19 was a major metabolite in the profiled urine and feces samples. Presence of large proportion of drug/drug-related material in feces suggested that the biliary excretion is a main elimination route of (3)H Nestorone. The distribution, metabolism, and excretion profiles of (3)H Nestorone obtained in this study provide a fairly good insight about its fate in women.
一种合成孕激素奈妥酮正在被开发用于女性避孕。本研究旨在确定放射性标记奈妥酮（3H 奈妥酮）在成年雌性大鼠体内的分布、代谢和排泄。大鼠经皮下（SC）注射 400μCi（3H 奈妥酮/kg BW）的单剂量。在规定的时间内确定其在血液、血浆和其他组织中的分布和浓度。检查排泄物中 3H 奈妥酮的消除情况。所有样品的放射性均通过液体闪烁计数器进行分析。通过 HPLC 和 LC/MS 分析血浆、尿液和粪便样品进行代谢产物分析。皮下注射 3H 奈妥酮后，血药和血浆中的放射性最大浓度（Cmax）分别在给药后 2 小时（Tmax）达到 58.1 和 95.5ng 当量（3H 奈妥酮/g。此后，药物浓度在 96 小时后通过末端消除半衰期（t1/2）为 15.6 小时而稳定下降。3H 奈妥酮衍生的放射性在 0.5 小时内广泛分布于大多数组织，并在给药后 2 小时达到最大浓度。大约 81.4%和 7.62%的给药剂量分别通过粪便和尿液排泄。体内代谢 3H 奈妥酮共产生 19 种代谢产物。其中，通过 HPLC 和 LC/MS 分析鉴定出两种代谢产物，即 17α-去乙酰奈妥酮（M9）和 4,5-二氢-17α-去乙酰奈妥酮（M19）。血浆样品的代谢产物分析表明，大部分循环放射性与未改变的母体药物和 M19 有关。M19 是已鉴定尿液和粪便样品中主要的代谢产物。粪便中存在大量药物/药物相关物质表明胆汁排泄是 3H 奈妥酮的主要消除途径。本研究中获得的 3H 奈妥酮的分布、代谢和排泄谱为其在女性体内的命运提供了相当好的见解。
