ABSTRACT
Toremifene was labelled to a specific activity of about 20 microCi/mmol with tritium at positions 3 and 5 in the para-substituted phenyl ring. At these positions tritium is not eliminated within the metabolic pathways. A mixture of unlabelled and labelled toremifene (5 or 10 mg/kg, 5 microCi/mg) was given i.v. or p.o. to Sprague-Dawley rats. The elimination of radioactivity was followed up by collecting urine and feces daily for 13 days. The elimination of toremifene which was similar after p.o. and i.v. administration took place mainly in the feces. About 70% of the total radioactivity was eliminated within 13 days, of this amount more than 90% in the feces. All applied radioactivity could be detected in three separate fractions according to the oxidative state of the side chain when counted by Berthold TLC Linear Analyzer. Each fraction was further separated into single metabolites by TLC or HPLC. Altogether 9 metabolites were identified and almost all methanol-extractable components were identified. The main metabolic pathways in the rat were 4-hydroxylation and N-demethylation. The side chain was further oxidized to alcohols and carboxylic acids. Small amounts of unchanged toremifene were found in the feces both after p.o. and i.v. administration indicating biliary secretion.
Subject(s)
Estrogen Antagonists/metabolism , Rats, Inbred Strains/metabolism , Tamoxifen/analogs & derivatives , Administration, Oral , Animals , Chlorine/metabolism , Chromatography, Thin Layer/methods , Dose-Response Relationship, Drug , Estrogen Antagonists/administration & dosage , Estrogen Antagonists/pharmacokinetics , Female , Injections, Intravenous , Mass Spectrometry/methods , Rats , Tamoxifen/administration & dosage , Tamoxifen/metabolism , Tamoxifen/pharmacokinetics , Toremifene , TritiumABSTRACT
The basic pharmacological and biochemical properties of a new antiestrogen, Fc-1157a, are described. Fc-1157a is bound specifically and with high affinity to estrogen receptors. The binding is competitive with estradiol. Fc-1157a treatment induces translocation of estrogen receptors from cytoplasm to nucleus. The turnover rate of nuclear estrogen receptors is markedly lower than with estradiol, but is more rapid than after tamoxifen. Fc-1157a is an almost pure antiestrogen in rat uterus, but has intrinsic estrogenic activity in mouse uterus. In animal experiments Fc-1157a has shown antitumor properties, which are described in the companion paper.
Subject(s)
Estrogen Antagonists , Tamoxifen/analogs & derivatives , Animals , Biological Transport/drug effects , Cell Nucleus/metabolism , Cytosol/metabolism , Estradiol/pharmacology , Female , Mice , Ovariectomy , Rats , Receptors, Estrogen/drug effects , Receptors, Estrogen/metabolism , Receptors, Progesterone/metabolism , Tamoxifen/pharmacology , Toremifene , Uterus/drug effectsABSTRACT
The antitumor effects of a new antiestrogen, Fc-1157a have been studied in vitro and in vivo. In vitro the effect of Fc-1157a was comparable to that of tamoxifen. The effect was dose-dependent, and at concentrations higher than 10(-6) mol/1 Fc-1157a induced real cell death of the MCF-7 cells. In DMBA-induced mammary cancer in rats Fc-1157a decreased the number of new tumors and inhibited the growth of existing tumors, these effects being statistically highly significant. The ratio of growing tumors to stable and regressing tumors was significantly decreased. Although these effects were slightly stronger with Fc-1157a than with tamoxifen, the difference between these two compounds was not statistically significant. Murine uterine sarcoma, an estrogen receptor-negative tumor, was resistant to tamoxifen, but was statistically significantly inhibited by high doses (100 and 200 mg/kg-1 day-1 for 5 days) of Fc-1157a. The antitumor effects of Fc-1157a are due mainly to the antiestrogenic activity. At high concentrations in vitro and at high doses in vivo Fc-1157a exerts antitumor effects some of which are different from those of tamoxifen and are directed even against estrogen receptor-negative tumors. The exact mechanism of the observed cytolytic effect at high doses is unknown.
