title: Metabolites, pharmacodynamics, and pharmacokinetics of tamoxifen in rats and mice compared to the breast cancer patient.
abstract: The metabolism of tamoxifen was examined in the rat, mouse, and human breast cancer patient. Large oral doses of tamoxifen (200 mg/kg) in the immature ovariectomized rat and mature mouse produced circulating levels of the parent compound, N-desmethyltamoxifen, and 4-hydroxytamoxifen quantifiable by HPLC separation, UV activation, and fluorescence detection. N-Desmethyltamoxifen and 4-hydroxytamoxifen serum levels in the mature ovariectomized mouse paralleled tamoxifen levels throughout a 96-hr time course after a single dose of tamoxifen. On the other hand, N-desmethyltamoxifen was the predominant serum metabolite after an equivalent dose of tamoxifen to the immature rat, but there was little 4-hydroxytamoxifen. Peak levels of tamoxifen occurred 3-6 hr after oral administration of tamoxifen in both species, whereas peak levels of N-desmethyltamoxifen in the immature rat did not occur until 24-48 hr. AUCs for tamoxifen and N-desmethyltamoxifen were approximately 4 times greater in the rat (57.5 and 111 micrograms.hr/ml, respectively) than the mouse (15.9 and 26.3 micrograms.hr/ml, respectively) after equivalent doses of tamoxifen (200 mg/kg). AUC of 4-hydroxytamoxifen for the rat (8.9 micrograms.hr/ml), however, was similar to that for the mouse (13.9 micrograms.hr/ml). The rate of elimination from serum was similar for tamoxifen, N-desmethyltamoxifen, and 4-hydroxytamoxifen in both the rat (t1/2 = 10.3, 12.1, and 17.2 hr, respectively) and the mouse (t1/2 = 11.9, 9.6, and 6 hr, respectively). Administration of large oral doses of tamoxifen (200 mg/kg) every 24 hr to mature ovariectomized mice or immature ovariectomized rats resulted in accumulation for the first 4 days.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Department of Human Oncology, University of Wisconsin Clinical Cancer Center, Madison 53792.
authors.forename: S P
authors.initials: SP
authors.lastname: Robinson
authors.forename: S M
authors.initials: SM
authors.lastname: Langan-Fahey
authors.forename: D A
authors.initials: DA
authors.lastname: Johnson
authors.forename: V C
authors.initials: VC
authors.lastname: Jordan
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D005260:Female; D006801:Humans; D051379:Mice; D008813:Mice, Inbred ICR; D010052:Ovariectomy; D051381:Rats; D011919:Rats, Inbred Strains; D013056:Spectrophotometry, Ultraviolet; D013629:Tamoxifen / Q000031:analogs & derivatives / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology; D014018:Tissue Distribution; D014599:Uterus / Q000378:metabolism
chemical_list: D013629:Tamoxifen; C016601:afimoxifene; C028787:N-desmethyltamoxifen