title: Metabolism of clomiphene in the rat. Estrogen receptor affinity and antiestrogenic activity of clomiphene metabolites.
abstract: Incubation of the nonsteroidal antiestrogen clomiphene with rat liver microsomes resulted in the formation of the 4-hydroxy-, N-desethyl-, and N-oxide metabolites, in qualitative contrast to results previously obtained analogously with rabbit microsomes, with which only the first two metabolites were detected. Metabolites were characterized by thin-layer chromatography in comparison with synthetic standards. They were similarly compared using low resolution electron ionization mass spectrometry, except for the N-oxide which was best characterized by fast atom bombardment mass spectrometry. Oral administration of clomiphene resulted in no detectable urinary elimination of the drug or its metabolites; 4-hydroxyclomiphene was the sole detectable elimination product in fecal extracts. The relative uterine cytosol estrogen receptor binding affinities, at 4 degrees, of 4-hydroxyclomiphene and the E-isomers of clomiphene, desethylclomiphene, and clomiphene N-oxide were, in turn, 331, 0.71, 0.62, and 0.88 (estradiol = 100). In the 3-day immature rat uterotropic assay, 4-hydroxyclomiphene had no significant uterotropic effect at doses up to 50 micrograms/day, but substantially inhibited that of estradiol (0.5 micrograms/day) at doses of 2 micrograms/day.
mesh_terms: D000818:Animals; D001711:Biotransformation; D002996:Clomiphene / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000494:pharmacology; D003600:Cytosol / Q000378:metabolism; D004958:Estradiol / Q000378:metabolism; D004965:Estrogen Antagonists; D005260:Female; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D013058:Mass Spectrometry; D008862:Microsomes, Liver / Q000378:metabolism*; D011817:Rabbits; D051381:Rats; D011919:Rats, Inbred Strains; D011959:Receptors, Estradiol; D011960:Receptors, Estrogen / Q000187:drug effects / Q000378:metabolism*; D014599:Uterus / Q000378:metabolism
chemical_list: D004965:Estrogen Antagonists; D011959:Receptors, Estradiol; D011960:Receptors, Estrogen; D002996:Clomiphene; D004958:Estradiol