ABSTRACT
The estrogen antagonists tamoxifen and monohydroxytamoxifen are also classified as partial estrogen agonists. In infantile rats, estradiol induced a single peak of uterine ODC activity at 6h following injection regardless of the extent of induction by various estradiol doses. By contrast, the timing of the ODC activity peak induced by tamoxifen and monohydroxytamoxifen was highly dependent upon the dosing conditions and was delayed to 18 h at lower tamoxifen doses. In immature rats, tamoxifen and monohydroxytamoxifen induced two peaks of uterine ODC activity resembling those induced by estradiol. Both ODC activity peaks were delayed by 9 h, without decreases in peak heights, by a 50-fold tamoxifen dose reduction. In all experiments the initial appearance of antiestrogen- and estradiol-induced ODC activity corresponded to initial uterine wet weight gain regardless of dosing condition. Thus, when dose-related temporal shifts are taken into account, tamoxifen and monohydroxytamoxifen are complete agonists with respect to induction of uterine weight gain and ODC activity.
Subject(s)
Estradiol/pharmacology , Estrogen Antagonists/pharmacology , Ornithine Decarboxylase/biosynthesis , Tamoxifen/analogs & derivatives , Tamoxifen/pharmacology , Uterus/anatomy & histology , Animals , Enzyme Induction , Female , Kinetics , Organ Size/drug effects , Rats , Rats, Inbred Strains , Uterus/drug effects , Uterus/enzymologyABSTRACT
Pharmacokinetics data on 2,4,5-T are used to illustrate design considerations, agent administration and sampling techniques required for single-animals studies in mice. Detailed methods for intravenous and intragastric delivery of chemicals are described, as are small volume (3 microliters) blood sampling techniques from tail vein and orbital plexus. A mouse metabolism cage is described that prohibits feed contamination of urine and feces, and also effectively segregates these elimination products. Techniques for blood, urine, and feces sample preparation and quality control assessments are also presented. Multi-sample blood concentration-time curves obtained from a single mouse are compared to data obtained using a single-sample design using may mice. While a single-animal, multiple-sample design requires the availability of microanalytical methods, it has many economic and practical advantages and results in a more accurate pharmacokinetic profile of the chemical in mice.
