Histologic changes in ovary, uterus, vagina, and mammary gland of mature beagle dogs treated with the SERM idoxifene.

BACKGROUND: Idoxifene is a selective estrogen receptor modulator similar to tamoxifen but is no longer in pharmaceutical development due to adverse genitourinary effects in the clinic. Histologic observations of the reproductive system and mammary glands are presented from female dogs treated with idoxifene for up to 12 months. METHODS: Studies were conducted as part of regulatory requirements to support clinical development. Idoxifene was given orally by capsule, once daily, for 1, 6, or 12 months to female Beagle dogs (n = 3 or 4/group) aged 11-14 months (start of dosing) at dosages 0, 0.03, 0.3, 1.5, or 3 mg/kg/day. Evaluations included the following: clinical observations, hematology, hemostasis, chemistry, toxicokinetics, and histology. RESULTS: Dose- and time-dependent findings were present in dogs given > or = 0.03 mg/kg/day and included abnormal vaginal discharge, minor increases of platelet and neutrophil counts, and microscopic observations in the ovary (atrophy and mesothelial [ovarian surface epithelium] hyperplasia), endometrium (edema, inflammation, glandular atrophy, squamous metaplasia, increased collagen), myometrium (edema, increased collagen), vagina (squamous hyperplasia, keratinization), and mammary gland (atrophy). CONCLUSION: Dogs given idoxifene exhibited estrogenic effects in ovary, uterus, and vagina but antiestrogenic effects in endometrial and mammary glands consistent with several observations in clinical trials in post-menopausal women treated with triphenylethylenes.

Enhancement of in vitro and in vivo microdialysis recovery of SB-265123 using Intralipid and Encapsin as perfusates.

This study was conducted to compare the ability of two potential microdialysis perfusates to enhance the recovery of SB-265123, a lipophilic, highly protein-bound compound, both in vitro and in vivo. Initial in vitro experiments established that the recovery of SB-265123 by microdialysis using normal saline as a perfusate was poor (1.7%). Different concentrations of Intralipid and Encapsin also were evaluated in an identical in vitro setting, to determine enhancement of recovery. In vitro recovery was enhanced to approximately 24 and 65% with 5 and 20% Intralipid, and to approximately 59 and 62% with 5 and 20% Encapsin, respectively. A rat in vivo study was conducted with 20% Encapsin to confirm the in vitro observations. In the in vivo study, 75-80% recovery of free SB-265123 was achieved using 20% Encapsin as a perfusate. The results from this study indicate that for SB-265123, a lipophilic, highly protein-bound molecule, Encapsin is an efficient recovery enhancer in vitro. The results from this investigation further demonstrate that a recovery enhancer may be useful for in vivo applications, even with a compound that is highly bound to plasma protein.