PHARMACOKINETICS AND BIOAVAILABILITY OF ST-1435 ADMINISTERED BY DIFFERENT ROUTES

The ovulation inhibiting potency of the synthetic progestin ST 1435 (N estorone(TM)) is high after parenteral administration and practically nil after oral administration. The purpose of this study was to determ ine the pharmacokinetic parameters of ST 1435 after single oral or int ravenous administration or after long-term treatment with subdermal im plants in women. After administration, as a single i.v, bolus, the pla sma disappearance rate of immunoreactive ST 1435 had two components wi th half-lives (mean +/- SE) of 3.5 +/- 0.5 and 83 +/- 14 min, respecti vely. The volume of distribution was 4.7 +/- 1.3 L/Kg and the metaboli c clearance rate was 55 +/- 6 L/Kg/d. After oval administration, the b ioavailability was about 10% of the dose. After chronic subdermal admi nistration, the plasmatic clearance was slower than following the acut e doses. These results show that ST 1435 has shouter half-lives and a faster clearance rate than progestins which bind SHBG. The large volum e of distribution indicates accumulation in the extravascular space an d was expected in view of the high affinity of ST 1435 for progesteron e receptors. The slower plasma elimination rate after chronic administ ration was attributed to the re-entry of a larger mass of drug from th e extravascular space, and/or accumulation of immunoreactive metabolit es with slower clearance than the parent steroid.