Single-dose Pharmacokinetics of Nestorone®, a potential female-contraceptive

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Article (peer-reviewed)

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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 of 3H Nestorone, the mean peak concentrations of radioactivity (Cmax) in the blood and plasma were 58.1 and 95.5 ng equiv. 3H Nestorone/g, respectively, at 2-h postdose (Tmax). Thereafter, the concentration of drug steadily declined through 96-h postdose with a terminal elimination half-life (t1/2) 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.