Plasma concentrations and receptor binding of RU 486 and its metabolites in humans

Heikinheimo Oskari, Kontula Kimmo, Croxatto Horacio, Spitz Irving, Luukkainen Tapani, Lähteenmäki Pekka

Resultado de la investigación: Article

93 Citas (Scopus)

Resumen

Using Chromosorb® chromatography and HPLC, we measured the plasma concentrations of RU 486, and its monodemethylated (RU 42633), didemethylated (RU 42848) and alcoholic nondemethylated (RU 42698) metabolites up to 72 h following oral ingestion of 100 mg of RU 486 by five female volunteers. The peak plasma level of RU 486 (4.5 μmol/l) occurred within 1 h after ingestion of the compound; at this point significant amounts of the metabolites were also present in the plasma. After the initial redistribution within 6 h the plasma concentrations of RU 486 and three of its metabolites measured remained stable for 24 h. Concentrations of the monodemethylated metabolite exceeded those of the parent steroid during the time period measured, whereas the concentrations of the didemethylated and alcoholic metabolites were lower than those of RU 486, but still notable. At 72 h the concentrations of all the four steroids were still in the micromolar range. The relative bincling affinities of these metabolites to human endometrial and myometrial progesterone receptors as well as to human placental glueocorticoid receptors were determined in vitro. The affinity of RU 486 for the human uterine progesterone receptor (Kd = 1.3 × 10-9 M for RU 486) was higher than that of progesterone but lower than that of ORG-2058, a potent synthetic progestin. The relative binding affinities of the monodemethylated, alcoholic and didemethylated metabolites to the progesterone receptor were 21, 15 and 9%, respectively, compared with the parent compound RU 486; each was lower than that of progesterone (43%). RU 486 had an approx. 4-fold higher relative bincling affinity to the glucocorticoid receptor than dexamethasone. Interestingly, the relative bincling affinities of the metabolites studied to the human glucocorticoid receptor exceeded those of dexamethasone or cortisol. Compared with the parent compound RU 486, they were 61, 48 and 45% for the monodemethylated, alcoholic and didemethylated metabolites, respectively; each was higher than that of dexamethasone (23%). The affinity of dexamethasone to the human glucocorticoid receptor was 1.6 × 10-9 M. These data indicate that the pool of certain metabolites of RU 486 may contribute to a significant extent to the antiprogestagenic (23-33%) and even greater extent to the antiglucocorticoid (47-61%) effects of RU 486.

Idioma originalEnglish
Páginas (desde-hasta)279-284
Número de páginas6
PublicaciónJournal of Steroid Biochemistry
Volumen26
N.º2
DOI
EstadoPublished - 1 ene 1987

Huella dactilar

Mifepristone
Metabolites
Plasmas
Dexamethasone
Glucocorticoid Receptors
Progesterone Receptors
Progesterone
Eating
Steroids
Progesterone Congeners
Chromatography
Hydrocortisone
Volunteers

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology

Citar esto

Oskari, Heikinheimo ; Kimmo, Kontula ; Horacio, Croxatto ; Irving, Spitz ; Tapani, Luukkainen ; Pekka, Lähteenmäki. / Plasma concentrations and receptor binding of RU 486 and its metabolites in humans. En: Journal of Steroid Biochemistry. 1987 ; Vol. 26, N.º 2. pp. 279-284.
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abstract = "Using Chromosorb{\circledR} chromatography and HPLC, we measured the plasma concentrations of RU 486, and its monodemethylated (RU 42633), didemethylated (RU 42848) and alcoholic nondemethylated (RU 42698) metabolites up to 72 h following oral ingestion of 100 mg of RU 486 by five female volunteers. The peak plasma level of RU 486 (4.5 μmol/l) occurred within 1 h after ingestion of the compound; at this point significant amounts of the metabolites were also present in the plasma. After the initial redistribution within 6 h the plasma concentrations of RU 486 and three of its metabolites measured remained stable for 24 h. Concentrations of the monodemethylated metabolite exceeded those of the parent steroid during the time period measured, whereas the concentrations of the didemethylated and alcoholic metabolites were lower than those of RU 486, but still notable. At 72 h the concentrations of all the four steroids were still in the micromolar range. The relative bincling affinities of these metabolites to human endometrial and myometrial progesterone receptors as well as to human placental glueocorticoid receptors were determined in vitro. The affinity of RU 486 for the human uterine progesterone receptor (Kd = 1.3 × 10-9 M for RU 486) was higher than that of progesterone but lower than that of ORG-2058, a potent synthetic progestin. The relative binding affinities of the monodemethylated, alcoholic and didemethylated metabolites to the progesterone receptor were 21, 15 and 9{\%}, respectively, compared with the parent compound RU 486; each was lower than that of progesterone (43{\%}). RU 486 had an approx. 4-fold higher relative bincling affinity to the glucocorticoid receptor than dexamethasone. Interestingly, the relative bincling affinities of the metabolites studied to the human glucocorticoid receptor exceeded those of dexamethasone or cortisol. Compared with the parent compound RU 486, they were 61, 48 and 45{\%} for the monodemethylated, alcoholic and didemethylated metabolites, respectively; each was higher than that of dexamethasone (23{\%}). The affinity of dexamethasone to the human glucocorticoid receptor was 1.6 × 10-9 M. These data indicate that the pool of certain metabolites of RU 486 may contribute to a significant extent to the antiprogestagenic (23-33{\%}) and even greater extent to the antiglucocorticoid (47-61{\%}) effects of RU 486.",
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Plasma concentrations and receptor binding of RU 486 and its metabolites in humans. / Oskari, Heikinheimo; Kimmo, Kontula; Horacio, Croxatto; Irving, Spitz; Tapani, Luukkainen; Pekka, Lähteenmäki.

En: Journal of Steroid Biochemistry, Vol. 26, N.º 2, 01.01.1987, p. 279-284.

Resultado de la investigación: Article

TY - JOUR

T1 - Plasma concentrations and receptor binding of RU 486 and its metabolites in humans

AU - Oskari, Heikinheimo

AU - Kimmo, Kontula

AU - Horacio, Croxatto

AU - Irving, Spitz

AU - Tapani, Luukkainen

AU - Pekka, Lähteenmäki

PY - 1987/1/1

Y1 - 1987/1/1

N2 - Using Chromosorb® chromatography and HPLC, we measured the plasma concentrations of RU 486, and its monodemethylated (RU 42633), didemethylated (RU 42848) and alcoholic nondemethylated (RU 42698) metabolites up to 72 h following oral ingestion of 100 mg of RU 486 by five female volunteers. The peak plasma level of RU 486 (4.5 μmol/l) occurred within 1 h after ingestion of the compound; at this point significant amounts of the metabolites were also present in the plasma. After the initial redistribution within 6 h the plasma concentrations of RU 486 and three of its metabolites measured remained stable for 24 h. Concentrations of the monodemethylated metabolite exceeded those of the parent steroid during the time period measured, whereas the concentrations of the didemethylated and alcoholic metabolites were lower than those of RU 486, but still notable. At 72 h the concentrations of all the four steroids were still in the micromolar range. The relative bincling affinities of these metabolites to human endometrial and myometrial progesterone receptors as well as to human placental glueocorticoid receptors were determined in vitro. The affinity of RU 486 for the human uterine progesterone receptor (Kd = 1.3 × 10-9 M for RU 486) was higher than that of progesterone but lower than that of ORG-2058, a potent synthetic progestin. The relative binding affinities of the monodemethylated, alcoholic and didemethylated metabolites to the progesterone receptor were 21, 15 and 9%, respectively, compared with the parent compound RU 486; each was lower than that of progesterone (43%). RU 486 had an approx. 4-fold higher relative bincling affinity to the glucocorticoid receptor than dexamethasone. Interestingly, the relative bincling affinities of the metabolites studied to the human glucocorticoid receptor exceeded those of dexamethasone or cortisol. Compared with the parent compound RU 486, they were 61, 48 and 45% for the monodemethylated, alcoholic and didemethylated metabolites, respectively; each was higher than that of dexamethasone (23%). The affinity of dexamethasone to the human glucocorticoid receptor was 1.6 × 10-9 M. These data indicate that the pool of certain metabolites of RU 486 may contribute to a significant extent to the antiprogestagenic (23-33%) and even greater extent to the antiglucocorticoid (47-61%) effects of RU 486.

AB - Using Chromosorb® chromatography and HPLC, we measured the plasma concentrations of RU 486, and its monodemethylated (RU 42633), didemethylated (RU 42848) and alcoholic nondemethylated (RU 42698) metabolites up to 72 h following oral ingestion of 100 mg of RU 486 by five female volunteers. The peak plasma level of RU 486 (4.5 μmol/l) occurred within 1 h after ingestion of the compound; at this point significant amounts of the metabolites were also present in the plasma. After the initial redistribution within 6 h the plasma concentrations of RU 486 and three of its metabolites measured remained stable for 24 h. Concentrations of the monodemethylated metabolite exceeded those of the parent steroid during the time period measured, whereas the concentrations of the didemethylated and alcoholic metabolites were lower than those of RU 486, but still notable. At 72 h the concentrations of all the four steroids were still in the micromolar range. The relative bincling affinities of these metabolites to human endometrial and myometrial progesterone receptors as well as to human placental glueocorticoid receptors were determined in vitro. The affinity of RU 486 for the human uterine progesterone receptor (Kd = 1.3 × 10-9 M for RU 486) was higher than that of progesterone but lower than that of ORG-2058, a potent synthetic progestin. The relative binding affinities of the monodemethylated, alcoholic and didemethylated metabolites to the progesterone receptor were 21, 15 and 9%, respectively, compared with the parent compound RU 486; each was lower than that of progesterone (43%). RU 486 had an approx. 4-fold higher relative bincling affinity to the glucocorticoid receptor than dexamethasone. Interestingly, the relative bincling affinities of the metabolites studied to the human glucocorticoid receptor exceeded those of dexamethasone or cortisol. Compared with the parent compound RU 486, they were 61, 48 and 45% for the monodemethylated, alcoholic and didemethylated metabolites, respectively; each was higher than that of dexamethasone (23%). The affinity of dexamethasone to the human glucocorticoid receptor was 1.6 × 10-9 M. These data indicate that the pool of certain metabolites of RU 486 may contribute to a significant extent to the antiprogestagenic (23-33%) and even greater extent to the antiglucocorticoid (47-61%) effects of RU 486.

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