Pharmacokinetics and bioavailability of ST 1435 administered by different routes

The ovulation inhibiting potency of the synthetic progestin ST 1435 (Nestorone™) is high after parenteral administration and practically nil after oral administration. The purpose of this study was to determine the pharmacokinetic parameters of ST 1435 after single oral or intravenous administration or after long-term treatment with sub-dermal implants in women. After administration, as a single i.v. bolus, the plasma disappearance rate of immunoreactive ST 1435 had two components with half-lives (mean ± SE) of 3.5 ± 0.5 and 83 ± 14 min, respectively. The volume of distribution was 4.7 ± 1.3 L/Kg and the metabolic clearance rate was 55 ± 6 L/Kg/d. After oral administration, the bioavailability was about 10% of the dose. After chronic subdermal administration, the plasmatic clearance was slower than following the acute doses. These results show that ST 1435 has shorter half-lives and a faster clearance rate than progestins which bind SHBG. The large volume of distribution indicates accumulation in the extra-vascular space and was expected in view of the high affinity of ST 1435 for progesterone receptors. The slower plasma elimination rate after chronic administration was attributed to the re-entry of a larger mass of drug from the extravascular space, and/or accumulation of immunoreactive metabolites with slower clearance than the parent steroid.