Effects Found in a One-Year Oral Toxicity Study in Sprague-Dawley Rats of a Novel 5-HT1A Receptor Partial Agonist for the Treatment of Anxiety in Humans

Abstract

A potent and selective serotonin (5-HT 1A ) partial agonist with potential as a human anxiolytic drug was given in oral doses of 0, 5, 15, or 50 mg/kg/day by gavage to Sprague-Dawley rats for 6 or 12 mo. Some animals were allowed 1 mo to recover after each treatment period. The 10-fold increase in dose resulted in a 20-fold increase in drug plasma concentration due to saturable first-pass metabolism. This resulted in disproportionately higher concentrations and greater bioavailability of the 15-and 50-mg/kg/day regimens. Drug exposure was associated with decreased spontaneous activity in the 15-and 50-mg/kg rats. The activity of these rats returned to normal during the recovery period. There were significant (p < 0.05) decreases in mean body weights during the study for 50-mg/ kg males, with improvement during the recovery periods. No biologically significant effects were noted in clinical laboratory parameters. Based on organ weight increases and histopathological evaluation, drug-related effects after 6 and 12 mo of treatment were in the pituitary (both sexes) and all treated female reproductive organs. In general, these effects persisted into periods of recovery, except for pituitary hyperplasia, which was not apparent following recovery after treatment for 6 mo. After treatment for 12 mo and the following recovery, there were significant increases in adrenal weights in the 15-and 50-mg/kg/day males with no morphological correlate. There was increased pituitary hyperplasia that persisted through the recovery period in all treated groups in both sexes, but there was no increase in pituitary neoplasms. In treated females, there was also morphologic evidence of persistent diestrus (estrogenic effect) evidenced by endometrial squamous metaplasia, increased corpora lutea, vaginal mucification, and decreased uterine size. The clinical and pathological changes seen with these 2 regimens were considered exaggerated pharmacological effects of the drug on serotonin receptor-rich organs.

Serotonin (5-HT1A-Receptor) Agonist-Induced Collecting Duct Vacuolation and Renal Papillary Necrosis in the Rat

“…Their mode of action is attributed mainly to stimulation of the 5-HTlA subtype of serotonin receptors (22). Buspirone is considered to be the prototype of this compound class (30). Ipsapirone represents also a serotonin (5-HT,,) receptor agonist and was recently under development as an anxiolytic drug.…”