Implications of tamoxifen metabolism in the athymic mouse for the study of antitumor effects upon human breast cancer xenografts.

The metabolism of tamoxifen in the human has been well established and may be important in the antiestrogenic activity of this agent. This study examines whether tamoxifen metabolism in the athymic mouse xenograft model is similar to tamoxifen metabolism in the breast cancer patient. Serum taken from athymic mice 24 h after a single large oral dose (200 mg/kg) of tamoxifen contained compounds corresponding to standards of tamoxifen, 4-hydroxytamoxifen, N-desmethyltamoxifen, 4-hydroxy-N-desmethyltamoxifen and tamoxifen-N-oxide when analyzed by high pressure liquid chromatography. The administration of large single doses (200 mg/kg) of 4-hydroxytamoxifen and N-desmethyltamoxifen either alone or in combination produced the expected peaks for the administered agents and a peak confirming the identity of 4-hydroxy-N-desmethyltamoxifen. 4-Hydroxy-N-desmethyltamoxifen was detected in serum from six out of 10 breast cancer patients receiving 10 mg bid of tamoxifen. These patients had tamoxifen, 4-hydroxytamoxifen and N-desmethyltamoxifen levels of 108 +/- 23, 2.6 +/- 0.5, and 238 +/- 58 ng/ml, respectively. Repeated large oral doses (200 mg/kg/day for 6 days) of tamoxifen to athymic mice produced a similar array of serum metabolites as seen after the single dose and in the breast cancer patient. However, levels of 4-hydroxytamoxifen (628 +/- 192 ng/ml) were similar to those of tamoxifen (441 +/- 208 ng/ml) whereas N-desmethyltamoxifen (1343 +/- 388 ng/ml) levels were 2-3 times greater. A similar pattern of metabolites was produced with a 50 mg/kg dose of tamoxifen although levels were considerably reduced. Subcutaneous administration of tamoxifen (200 mg/kg/day for 6 days) produced serum levels of the parent compound (120 +/- 19 ng/ml) in the same range as tamoxifen levels in the breast cancer patient. However, although N-desmethyltamoxifen was the major metabolite, levels (115 +/- 18 ng/ml) were only equivalent to those of tamoxifen itself and 4-hydroxytamoxifen levels (26 +/- 5 ng/ml) were appreciably higher than the breast cancer patient. Lowering the dose of tamoxifen (50 mg/kg) administered s.c. produced not only lower circulating tamoxifen levels (41 +/- 3 ng/ml) but also changed the metabolite profile. Rather than N-desmethyltamoxifen levels equivalent to those of tamoxifen, as seen with the higher dose, they were reduced to the level of 4-hydroxytamoxifen (7 +/- ng/ml).(ABSTRACT TRUNCATED AT 400 WORDS)