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)