DOSE-RESPONSE RELATIONSHIPS OF RU-486

Clinical experience has indicated that the effects of RU 486 can be divided into dose-dependent and dose-independent effects. Examples of the dose-dependent effects include the antiglucocorticoid effects of RU 486, whereas pregnancy termination or dilatation of the cervix can be considered dose-independent with the various regimens tested so far. Following oral intake in man, the serum levels of RU 486 are in the micromolar range, and the half-life is approximately 30 hours. The concentrations of RU 486 in myometrial tissue are approximately one-third of those measured in serum. However, due to saturation of alpha 1-acid glycoprotein (AAG), the serum binding protein for RU 486, the serum levels remain similar within the dose range of 100-800 mg of RU 486. The unbound RU 486 is metabolized by two-step demethylation or by hydroxylation. The demethylated and hydroxylated metabolites of RU 486 retain considerable affinities of 9-21% towards the human progesterone receptor, and 45-61% towards the human glucocorticoid receptor (RU 486=100%), suggesting a biological role for the metabolites. Rat serum lacks a specific binding protein for RU 486. Even though the levels of RU 486 in rat adipose tissue are 40 times as high as those seen in serum, the concentrations of RU 486 in rat brain are only 28% of the serum levels. This indicates that diffusion of RU 486 into the central nervous system is restricted by the blood-brain barrier. Hence, the dose-dependency of certain centrally mediated effects of RU 486 might be explained by the limited diffusion of RU 486 into hypothalamic/hypophyseal sites, which seem to be reached only after ingestion of high doses of RU 486. However, the peripheral effects of RU 486, such as termination of pregnancy, are mediated via steroid receptors in target tissues. This suggests that similar biological effects can be attained at considerably lower doses than the ones currently in use.