Metabolism and serum binding of RU 486 in women after various single doses.

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.