Mode of action of I.C.I. 46,474 in preventing implantation in rats.

Abstract

SUMMARY Trans-1-(p-β-dimethylaminoethoxyphenyl)-1,2-diphenylbut-1-ene (I.C.I. 46,474), given by mouth, was most effective in terminating early pregnancy in rats on the fourth day after mating. A single intravenous dose was effective on day 4 but even early on day 5 large doses had little effect. A single oral dose on day 1 or 2 sufficient to prevent implantation completely, caused accelerated tubal transport of the eggs and their premature expulsion from the uterus. This was partially blocked by progesterone and appears to be an oestrogenic effect. The corresponding dose on day 3 or 4 did not affect egg transport or development. After giving the compound on day 4, substantial but diminishing numbers of unimplanted eggs were recovered from the uterus up to day 11 of 'pregnancy'. Such blastocysts could be induced to implant in a proportion of rats by giving a single large injection of oestrogen at the same time as the compound (on day 4) or a progressively smaller dose up to day 11. These results support the hypothesis (Harper & Walpole, 1966) that I.C.I. 46,474 can prevent implantation in rats by counteracting the 'oestrogensurge' on day 4 necessary for its induction. They further suggest that the compound persists for some days in the uterus.