Journal Article

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 (^3H Nestorone) in adult female rats. Rats were injected subcutaneously (S.C.) with a single dose of 400 µCi ^3H 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 ^3H 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 ofH Nestorone, the mean peak concentrations of radioactivity (C_max) in the blood and plasma were 58.1 and 95.5 ng equiv. ^3H 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. ^3H 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 ^3H Nestorone resulted into a total of 19 metabolites. Among them, two metabolites viz., 17α-deacetyl-Nestorone (M9) and 4,5-dihydro-17α-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 ^3H Nestorone. The distribution, metabolism, and excretion profiles of ^3H Nestorone obtained in this study provide a fairly good insight about its fate in women.