Biomarker levels in hormonally sensitive female F-344 rat and beagle dog tissues after treatment with SR16157, a selective estrogen receptor modulator (SERM)

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SR16157 is a potent in vitro inhibitor of estrone sulfatase (ES) and antitumor agent in mouse xenograft breast cancer models. Preliminary safety studies show that SR16157 is relatively nontoxic (MTD >500 mg/kg) in rats and dogs. In the current studies, tissue levels of estrogen, estrone, estradiol, and estrone sulfate were quantified using EIA, and hepatic estrone sulfatase (ES) activities were determined. Rats received SR16157 by daily gavage for 14 days at 50, 200 or 1000 mg/kg (300, 1200, 6000 mg/m²). Dogs received a single dose of SR16157 by IV (2 mg/kg, 40 mg/m²) or orally (capsule or gavage 20 and 200 mg/kg, 400 and 4000 mg/m²). Blood was collected for evaluation of circulating serum biomarker and plasma drug levels. Liver, ovaries, uterus, vagina, mammary fat, fallopian tubes and cervix (dog only) were flash frozen at necropsy. In rats, mortality was observed at 200 and 1000 mg/kg. Dose related decreases were observed in circulating lymphocytes and lymphoid depletion in spleen, thymus and regional lymph nodes. Hepatic ES was almost completely blocked in SR16157-treated groups, and dose-related reductions in estradiol were observed in liver and ovaries. In dogs, emesis was observed at 200 mg/kg (both oral routes). By 6 hr post dose, hepatic ES was completely inhibited in SR16157-treated groups and activity remained decreased (<5% of control) for the entire 48 hr time course. Treatment-related increases were observed in hepatic and uterine estrone levels. Estrone sulfate was also increased in liver at 6 hr only. Dose and time-related increases were observed for serum estrone levels, peaking at 8 hr. Oral bioavailability in female rats (50 mg/kg; 300 mg/m²) was 61% (gavage) and in female dogs (20 mg/kg; 400 mg/m²) was 27% after gavage or ∼100% after capsule administration. In conclusion SR16157 has excellent oral bioavailability with minimal toxicity to rats and dogs. Furthermore, ES inhibition is a very sensitive indicator of the pharmacologic action of SR16157. Work supported by NCI Contract N01-CM-42203.