TY - JOUR
T1 - Metabolism and serum binding of RU 486 in women after various single doses
AU - Heikinheimo, O.
AU - Laähteenmaäki,, P. L.A.
AU - Koivunen, E.
AU - Shoupe, D.
AU - Croxatto, H.
AU - Luukkainen, T.
AU - Laähteenmaäki, P.
PY - 1987/1/1
Y1 - 1987/1/1
N2 - The metabolism of RU 486 was studied in female volunteers following a single oral administration of 100, 400, 600 or 800 ing 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 hydroxyl-ation. 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 tower-capacity reaction. In each group of different dosage, positive correlations were found between the individual mean α 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 /tM. In serum at 40 nM and 2.5 /tM 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.
AB - The metabolism of RU 486 was studied in female volunteers following a single oral administration of 100, 400, 600 or 800 ing 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 hydroxyl-ation. 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 tower-capacity reaction. In each group of different dosage, positive correlations were found between the individual mean α 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 /tM. In serum at 40 nM and 2.5 /tM 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.
KW - Antiprogesterone RU 486
KW - α1-acid glycoprotein
UR - http://www.scopus.com/inward/record.url?scp=0023250459&partnerID=8YFLogxK
U2 - 10.1093/oxfordjournals.humrep.a136554
DO - 10.1093/oxfordjournals.humrep.a136554
M3 - Article
C2 - 3654927
AN - SCOPUS:0023250459
SN - 0268-1161
VL - 2
SP - 379
EP - 385
JO - Human Reproduction
JF - Human Reproduction
IS - 5
ER -