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Distribution of RU 486 and Its Demethylated Metabolites in Humans^*

Steroid Research Laboratory, Department of Medical Chemistry, University of Helsinki Helsinki, Finland

Address all correspondence and requests for reprints to Oskari Heikinheimo, Steroid Research Laboratory, Department of Medical Chemistry, University of Helsinki, Siltavuorenpenger 10A, SF-00170 Helsinki, Finland.

The concentrations of RU 486 and its demethylated metabolites were determined by RIA in samples of myometrium, abdominal adipose tissue, and serum, which were collected at hysterectomies performed 12–15 h after oral administration of 200 mg RU 486. The RU 486 concentrations in myometrium were similar in the five women studied, with a mean of 148 ± 58 (±SD) ng/g (344 ± 135 pmol/g). The adipose tissue RU 486 levels varied more, the mean concentration being 447 ± 191 ng/g (1041 ± 445 pmol/g). The serum RU 486 concentrations ranged from 175-899 ng/ml [mean, 396 ± 259 ng/mL (922 ± 603 nmol/L)]. In these women the nonproteinbound fraction of [6,7-³H]RU 486 varied from 1.4–3.1% (mean, 2.3%). The approximate concentrations of the combined monoand didemethylated metabolites of RU 486 were 1.4, 3.1, and 5.2 times higher in adipose tissue, myometrial tissue, and serum, respectively, than those of the parent RU 486. In vitro, rapid and nonsaturable accumulation of [6,7-³H]RU 486 from phosphate buffer into adipose tissue was inhibited by the addition of ofi-acid glycoprotein, the specific serum transport protein for RU 486, to the buffer medium. Accumulation of [6,7-³H]RU 486 in myometrial specimens was poor. The enterohepatic cycling of RU 486 was assessed in four normal subjects by repetitive intake of charcoal subsequent to ingestion of 200 mg RU 486. Compared to other normal subjects, the serum levels and areas under the concentration curves were lower and t values shorter in the group given charcoal, suggesting that in vivo RU 486 may be partly pooled in the enterohepatic cycle. Our studies suggest that despite the low volume of distribution and the effective serum binding of RU 486, the myometrial and adipose tissue concentrations of RU 486 and its metabolites were similar (10^–9–10^–10 mol/g) after oral intake of RU 486.

^* This work was supported by the Cancer Society of Finland, the Paulo Foundation, the Ford Foundation, and the Mellon Foundation. The content of this paper does not necessarily reflect the policy of any of the funding sources.

Received June 21, 1988.

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