Single-dose pharmacokinetics of Nestorone, a potential female-contraceptive.

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.

Identification of 19-norprogesterone in pregnant rat urine.

The existence of biosynthetic pathways leading to the formation of 19-nor-androgens and corticoids have been established in animals and humans. The exact biologic function of the products of these pathways in vivo has yet to be established; however, it has been shown that they possess pronounced biologic activity when administered exogenously. This report describes the identification of 19-nor-progesterone isolated from the urine of pregnant rats. The procedures used included isolation as the underivatized material and methoxime derivative by thin-layer and high-performance chromatography. The identity was further confirmed by gas chromatography/mass spectral analysis of the isolated product as the 3,20-bis-methoxime derivative. The spectra obtained from the urinary product and the authentic 19-norprogesterone-3,20-bis-methoxime were identical. A possible biologic role for 19-norprogesterone or its precursors is discussed.