Metabolism of clomiphene in the rat. Estrogen receptor affinity and antiestrogenic activity of clomiphene metabolites.
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.
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
D004965:Estrogen Antagonists; D011959:Receptors, Estradiol; D011960:Receptors, Estrogen; D002996:Clomiphene; D004958:Estradiol