THE PROGESTIN ST-1435 - RAPID METABOLISM IN MAN

Parenterally administered ST 1435 (Nestorone(TM) is highly potent for contraception, and ovulation can be inhibited with very low serum leve ls of ST 1435. Orally administered ST 1435 is ineffective in various l aboratory animals, presumably due to extensive first-pass metabolism. Thus, ST 1435 has been proposed for lactational contraception, to be m etabolized by the suckling infant. We have studied the metabolism of S T 1435 in female volunteers following oral (10 mg), intravenous (iv) ( 0.1 mg) and transdermal (4.5-9.0 mg) routes of ST 1435 administration. Preliminary studies using rats were performed to develop the methodol ogy of high performance-liquid chromatography (HPLC) fractionation and ST 1435-RIA detection. Rat portal serum revealed 4 distinct peaks of immunoreactive material with the retention times (Rt's) of 7.5, 10, 14 .5 and 17.5 min (ST 1435 = 10 min). In systemic serum, only the peak w ith the Rt of 7.5 min could be detected. Therefore, orally administere d ST 1435 is very effectively metabolized by the rat liver; this also explains the previously observed lack of biological effects of oral ST 1435. Following oral administration of ST 1435 to two women, the Rt o f the major peak was 10 min. The magnitude of the ST 1435 peak decreas ed rapidly, and at 24h following ingestion, no ST 1435 could be detect ed by this method. The t(1/2) of ST 1435 was similar to 1-2h. In addit ion, two minor peaks with Rt's of 4.5 and 16 min could be detected wit h the ST 1435 RIA at 1-4h following oral ingestion. Competitive recept or binding assays using the human uterine progesterone receptors (hPR) revealed that the ST 1435 fraction exhibits strong binding affinity t owards the hPR; thus, in the human, a small fraction of biologically a ctive ST 1435 seems to escape from the first-pass metabolism following oral intake. Following iv and transdermal administration of ST 1435, the only detectable peak with ST 1435-RIA was that of ST 1435. Similar magnitude of the ST 1435 peaks following oral administration of 10 mg and iv administration of 0.1 mg indicated that the bioavailability of ST 1435 is low. These data seem to confirm the suspicion that orally administered ST 1435 is also rapidly metabolized in the human, therefo re encouraging further evaluation of ST 1435 during lactation. However the rapid metabolism seen after oral intake can be successfully circu mvented by sustained parenteral administration of ST 1435.