Parenterally administered ST 1435 (Nestorone™
) is highly potent for contraception, and ovulation can be inhibited with very low
serum levels of ST 1435. Orally administered ST 1435 is ineffective in various laboratory
animals, presumably due to extensive first-pass metabolism. Thus, ST 1435 has been
proposed for lactational contraception, to be metabolized by the suckling infant.
We have studied the metabolism of ST 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 methodology 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 with the Rt of 7.5 min could be detected. Therefore,
orally administered 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 of the major peak was
10 min. The magnitude of the ST 1435 peak decreased rapidly, and at 24h following
ingestion, no ST 1435 could be detected by this method. The t
of ST 1435 was ~ 1–2h. In addition, two minor peaks with Rt's of 4.5 and 16 min could
be detected with the ST 1435 RIA at 1–4h following oral ingestion. Competitive receptor
binding assays using the human uterine progesterone receptors (hPR) revealed that
the ST 1435 fraction exhibits strong binding affinity towards the hPR; thus, in the
human, a small fraction of biologically active 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, therefore encouraging further evaluation of ST 1435 during lactation.
However, the rapid metabolism seen after oral intake can be successfully circumvented
by sustained parenteral administration of ST 1435.