Metabolism and serum binding of Ru 486 in women after various single doses*

Abstract

The metabolism of RU 486 was studied in female volunteers following a single oral administration of 100, 400, 600 or 800 mg of RU 486. The serum concentrations of RU 486 were generally not affected by the dose within the range examined and they stayed at micromolar concentrations during the 48 h studied. RU 486 was metabolized extensively in a dose-dependent manner by two-step demethylation, and by hydroxylation. Serum levels of the monodemethylated metabolite always exceeded those of RU 486. The concentrations of the didemethylated and hydroxylated metabolites equalled or exceeded those of RU 486 when the ingested dose was 400 mg or more. Monodemethylation and hydroxylation were rapid high-capacity reactions, whereas didemethylation was a lower-capacity reaction. In each group of different dosage, positive correlations were found between the individual mean alpha 1-acid glycoprotein (AAG) concentrations and the peak concentration of RU 486 measured at 1-2 h, versus the plateau concentration of RU 486 measured at 6 h. The in-vitro studies showed that the specific serum transport protein of RU 486, AAG, was saturated by RU 486 concentrations exceeding 2.5 microM. In serum at 40 nM and 2.5 microM RU 486 concentrations, 2.7% and 2.4%, respectively, of [3H]RU 486 was not protein bound. Purified AAG in phosphate buffer was able to bind [3H]RU 486 in a similar manner to that of serum. Thus our results suggest that AAG regulates in part the serum concentrations of RU 486, and RU 486 exceeding the specific serum transport capacity is effectively metabolized.

Antioxidant: a new role for RU-486 and related compounds.

“…Single dose studies have suggested that in human serum RU-486 is bound to ac-l-acid glycoprotein and the plasma concentration may be limited by the saturation of this protein (2,18). On the other hand, onapristone does not appear to bind to this protein (1).…”

“…Despite considerable progress in the understanding of the biochemistry and molecular biology of steroid hormone receptors and the interaction of antiprogestins with the receptor (1, 2, 14-17), very little is known about the potential nonhormonal actions of these compounds. It is efficiently absorbed from the intestine and plasma concentrations reach micromolar amounts (1,2,18,19). We anticipated that RU-486 may interact with an oxidation system and may exhibit potent antioxidant properties, based on its chemical nature, its similarity to the antioxidant, Lazaroid U-74,500A (a lipophilic dimethyl-or ethyl-amino group), and the formation of mono-and di-demethylated and hydroxylated metabolic products (20,21).…”

In vitro antiprogestational/antiglucocorticoid activity and progestin and glucocorticoid receptor binding of the putative metabolites and synthetic derivatives of CDB-2914, CDB-4124, and mifepristone

“…The N-monodemethylated product is the primary metabolite, and after oral administration of 100-800 mg mifepristone, its concentration exceeds that of the parent compound [21,22]. At higher dose levels of mifepristone (>400 mg), the other metabolites also accumulate at high concentrations [21]. Both the demethylated and hydroxylated metabolites are eventually further degraded and excreted into bile [11].…”

A prospective comparative study of oral and vaginal misoprostol after pre-treatment with single dose of mifepristone for second trimester abortion

“…28,29 The adverse effects observed after use of mifepristone are mainly gastrointestinal, including nausea, vomiting, abdominal pain and skin rashes. 30 Introduction of Misoprostol in late 70's revolutionised the management of termination of pregnancy. It is known that prostaglandins stimulate uterine contractility at any stage of pregnancy and also cause cervical ripening and dilatation.…”