Metabolites, pharmacodynamics, and pharmacokinetics of tamoxifen in rats and mice compared to the breast cancer patient

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 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 μg·hr/ml, respectively) than the mouse (15.9 and 26.3 μg·hr/ml, respectively) after equivalent doses of tamoxifen (200 mg/kg). AUC of 4-hydroxytamoxifen for the rat (8.9 μg·hr/ml), however, was similar to that for the mouse (13.9 μg·hr/ml). The rate of elimination from serum was similar for tamoxifen, N-desmethyltamoxifen and 4-hydroxytamoxifen in both the rat (t( 1/2 )) = 10.3, 12,1, and 17.2 hr respectively) and the mouse (t( 1/2 ) = 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. After this accumulation, a plateau was reached in both species, with serum N-desmethyltamoxifen levels about 1.5 to 2 times that of tamoxifen. Steady-state serum levels of 4-hydroxytamoxifen in the mature mouse were similar to those of the N-desmethyltamoxifen metabolite, whereas low levels of 4-hydroxytamoxifen are present in the immature rat. Examination of tamoxifen metabolites in the mature rat indicates a similar pattern as in the immature animal, which suggests that 4-hydroxylation pathways do not develop with age. In human breast cancer patients on chronic tamoxifen treatment, the metabolite profile is similar to that seen in the mature and immature rat. Levels of tamoxifen, N-desmethyltamoxifen, and 4-hydroxytamoxifen in a patient receiving 170 mg of tamoxifen b.i.d. were equivalent to those in the immature rat receiving a daily dose of 200 mg/kg po, whereas a patient receiving 30 mg b.i.d. had similar levels of tamoxifen and N-desmethyltamoxifen as the mature mouse receiving daily doses of 200 mg/kg po; however, 4-hydroxytamoxifen levels were markedly different. Tamoxifen and metabolite profiles in the tissues of the rat and mouse following both large single and multiple oral doses of tamoxifen (200 mg/kg) were similar to those in the serum, although tissue levels had not reached a plateau by day 7. Liver and uterine levels per mg tissue were consistently higher in both species than skeletal muscle levels and more than 100 times greater than serum levels at day 7 (assuming 1 g of tissue is equivalent to 1 ml of serum). This study indicates that the rat is similar to the human in the way large oral doses of tamoxifen are metabolized and may be more representative of the breast cancer patient than the mouse for toxicology and antitumor studies.