Pharmacokinetic interpretation of toxicity tests in rats treated with oestradiol valerate in the diet.
Oestrogen concentrations (oestradiol = E2 and oestriol = E3) were determined in plasma and liver tissue of female rats before, during and after treatment with two different doses (1.2 and 12.0 mg/kg/d) of oestradiol valerate (E2-val) given in the feed over 27 days. The oral bioavailability of E2 was determined in a pharmacokinetic study in which rats received a single intramuscular administration of E2-val. The aim of the present investigation was to support the evaluation of the results of a previous 90 weeks chronic toxicity and tumorigenicity study in rats where the same dosages were administered. The bioavailability was approximately 0.5%; the systemic body burden of exogenous E2 was 1.6 fold, the endogenous E2 burden at the low, and 9 fold at the high dose. Despite these low values, distinct systemic effects were noted. At 1.2 mg/kg/d a marked decrease in food consumption and body weight gain occurred in the 27 day study as well as in the chronic study. In addition, in the latter study mortality increased from the low dose onwards and was complete at the high dose after 72 weeks. The incidence of pituitary adenoma increased. The results indicate that theoretically rats are far more sensitive towards exogenous oestradiol treatment than humans.
Kuhnz
W
W
Research Laboratories, Schering AG, Berlin, FRG.
Putz
B
B
D000818:Animals; D001682:Biological Availability; D001835:Body Weight / Q000187:drug effects; D004032:Diet; D004435:Eating / Q000187:drug effects; D004958:Estradiol / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000633:toxicity; D005260:Female; D007273:Injections, Intramuscular; D008297:Male; D010902:Pituitary Gland / Q000033:anatomy & histology / Q000187:drug effects; D011863:Radioimmunoassay; D051381:Rats; D011919:Rats, Inbred Strains
D004958:Estradiol