Dose-response relationships of RU 486.

Abstract:

: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. :RU-486 has both dose-dependent effects and dose-independent effects. Acute treatment of single doses of at least 400 mg RU-486 increase secretion of adrenocorticotropic hormone. 50-100 mg RU-486 activate the hypothalamo-pituitary-adrenal (HPA) axis. Pregnancy termination and dilatation of the cervix are dose-independent effects. Oral ingestion in humans results in RU-486 serum concentrations in the micromolar range with a half-life of about 30 hours. RU-486 levels in myometrial tissue are about 33% lower than those in the serum. 2-step demethylation or hydroxylation metabolizes unbound R-486. The resulting RU-486 metabolites are able to bond strongly to the human progesterone receptor and to the human glucocorticoid receptor (9-21% and 45-61%, respectively, vs. 100% for RU-486), indicating that the metabolites have a biological role. Research in rats suggests that the blood-brain barrier prevents the diffusion of RU-486 into the central nervous system. Limited diffusion of RU-486 into hypothalamic/hypophyseal sites may account for the dose-dependency of certain centrally mediated effects of RU-486. Oral intake of high doses of RU-486 appears to be the only route to hypothalamic/hypophyseal sites. Steroid receptors in target tissues, e.g., endometrium, mediate RU-486's indirect effects, e.g., pregnancy termination, indicating much lower doses of RU-486 than are now being used can have the same effects.

journal_name

Ann Med

journal_title

Annals of medicine

authors

Heikinheimo O,Kekkonen R

doi

10.3109/07853899309147861

subject

Has Abstract

pub_date

1993-02-01 00:00:00

pages

71-6

issue

1

eissn

0785-3890

issn

1365-2060

journal_volume

25

pub_type

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