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.

A potent and selective serotonin (5-HT1A) 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.

Metabolism of the anticoagulant peptide, MDL 28,050, in rats.

Rats were each administered a 9 mg/kg iv bolus dose of a 3H-labeled decapeptide anticoagulant, MDL 28,050. Tritium was eliminated rapidly with approximately 50% of the dose recovered in urine within the first 6 hr. Renal excretion accounted for 68% of the dose, whereas fecal excretion accounted for 16% of the dose. Continuous flow fast atom bombardment mass spectrometry was used to identify the major urinary metabolites of MDL 28,050. Trace amounts of parent drug were found, and other biotransformation products indicated that hydrolysis had occurred at four peptide bonds. Two initial sites of hydrolysis were identified as 4I-5P and 6E-7E, which resulted in the peptide fragments Suc-Y-E-P-I-OH + P-E-E-A-Cha-E-OH and Suc-Y-E-P-I-P-E-OH + E-A-Cha-E-OH, respectively. Further metabolism of these fragments resulted in the N-terminal pentapeptide and the C-terminal dipeptide.

Chronic toxicity studies with vigabatrin, a GABA-transaminase inhibitor.

The GABA-transaminase inhibitor, vigabatrin, has been shown to have a rather low degree of acute toxicity in several animal species. Oral administration of the drug at 1,000 mg/kg/day for 2-4 weeks caused decreased food consumption and weight loss with resultant prostration and death in both rats and dogs. Dosages of 200 mg/kg/day were tolerated for a year without clinical signs in dogs, although rats suffered reduced weight gains and convulsions after 3-4 months when given the drug in the diet. The convulsions continued to occur frequently throughout the one-yr study, but abated 3-4 months after cessation of treatment. The only consistent histopathologic evidence of toxicity in rats and dogs has been the finding of intramyelinic edema (microvacuolation) in the brain, most notably in certain areas of white matter (cerebellum, reticular formation and optic tract in rats and columns of fornix and optic tract in dogs). No lesions were found in the spinal cord or peripheral nervous system. It took several weeks for the microvacuolation to develop, even at high dosages, but it did not continue to progress thereafter, even though a slight effect was noted at dosages as low as 30-50 mg/kg/day after one yr of treatment. The intramyelinic edemia disappeared within a few weeks after treatment was withdrawn. No residual effects were observed in dogs, whereas rats exhibited swollen axons and microscopic mineralized bodies in the cerebellum. Monkeys exhibited no adverse clinical effects except for occasional loose stools at 300 mg/kg/day. After 16 months of oral treatment at 300 mg/kg/day any suggestion of intramyelinic edema was considered to be equivocal, and there was no evidence of any effect in the 50 or 100 mg/kg/day monkeys after 6 yr of treatment. Higher doses caused chronic diarrhea, thus limiting the dosage in this species. Vigabatrin was shown to be well absorbed in rat, dog and man, whereas dose-limited absorption occurred in the monkey. Metabolism is practically nil in all 4 species and the primary elimination pathway is by glomerular filtration. Because vigabatrin is an irreversible inhibitor of GABA-transaminase and the enzyme has a slow turnover rate, plasma levels of the drug are not indicative of its pharmacologic activity. For this reason cerebrospinal fluid levels of GABA and vigabatrin were evaluated, with considerable species differences being noted. The significance of these differences in relation to the differences in toxic response is discussed.

The fate of ultra-low viscosity 14C-hydroxypropyl methylcellulose in rats following gavage administration.

The disposition of 14C-Hydroxypropyl methylcellulose (HPMC) with a viscosity of 2.25 centipoise was studied in male and female Sprague-Dawley rats following a single 500 mg/kg body weight gavage dose, or five consecutive daily doses. Recoveries for the single dose were: feces, greater than 99%; urine, approximately 1%; carcass and tissues, approximately 0.2%; expired air, 0.07%; and bile, 0.05%. Plasma radioactivity had a monophasic excretion half-life of approximately 2 hours for either sex. The majority of the residual radioactivity in the tissues was found in the gastrointestinal tract. The absorbed radioactivity in the urine, based on thin layer chromatography (TLC) analyses, represented methyl ethers of glucose and oligomers; this amounted to 0.56% recovered in a study in which urine samples were isolated from possible contamination by radioactivity in the feces. The 0.56% correlated well with the 0.53% portion of the original dosing solution which consisted of cellulose units with an average molecular weight of less than 1000. Recovery of radioactivity in the feces of rats on the 5-day dosing regimen was 97% and 102% for males and females, respectively, without any evidence for accumulation in tissues. Approximately 1% was recovered in the urine. Thus, the results of this work show that ultra-low viscosity 2.25 centipoise HPMC was only minimally absorbed with essentially all of a single 500 mg/kg gavage dose, or 5 daily consecutive doses, being excreted unabsorbed in the feces.