COMPARATIVE PROGESTATIONAL ACTIVITY OF NORGESTIMATE, LEVONORGESTREL-OXIME AND LEVONORGESTREL IN THE RAT AND BINDING OF THESE COMPOUNDS TO THE PROGESTERONE-RECEPTOR

The progestational activity of norgestimate (NORG), levonorgestrel-oxi me (LNG-oxime) and levonorgestrel (LNG) were compared in a pregnancy m aintenance study in rats. The compounds were administered subcutaneous ly to pregnant rats at several doses, blood samples were collected rep eatedly, and the concentration of LNG was measured in these samples. I t could be demonstrated that following the administration of NORG and LNG-oxime, LNG was a major metabolite present in the serum. The pharma cological response in rats treated with NORG and LNG-oxime could be re lated to she systemic exposure of these animals to metabolically deriv ed LNG. Thus, both NORG and LNG-oxime can be regarded as pro-drugs of LNG, the latter being almost exclusively responsible for the pharmacol ogical activity of both pro-drugs. This notion was further supported b y studies on the comparative binding affinity of these compounds to ra bbit and human progesterone receptor (PR). LNG exhibited the highest b inding affinity of the compounds studied. Relative binding affinity (R BA) values of LNG using progesterone as reference (100%) were found to be 125% for rabbit PR (rPR), 143% for human uterine PR (hPR) and 125% for recombinant hPR, respectively. In contrast to LNG, NORG exhibited only a low affinity to the PR, which is documented by RBA values of 1 .2% for rPR, 3.2% for uterine hPR and 9% for recombinant hPR. The corr esponding values of LNG-oxime were 30% (rPR), 20% (uterine hPR) and 18 % (recombinant hPR), respectively. Thus, the combined experimental evi dence of the present study does not support the view of NORG being a p rogestogen on its own as has been suggested by others.