Plasma concentrations and pharmacokinetics of phenylalanine in rats and mice administered aspartame.

Aspartame (L-aspartyl-L-phenylalanine methyl ester) is an esterified, dipeptide sweetener that is rapidly and completely metabolized in the gastrointestinal tract to phenylalanine, aspartic acid and methanol. The pharmacokinetics of phenylalanine (PHE) and tyrosine (TYR) were examined following the administration of oral doses of aspartame (APM) to fasted male Sprague-Dawley rats (0, 50, 100, 200, 500 and 1,000 mg/kg) and CD-1 mice (0, 100, 200, 500, 1,000 and 2,000 mg/kg). Peak plasma PHE/large neutral amino acid (LNAA) ratios were calculated. Maximal plasma PHE and TYR concentrations were observed within 1 h after dosing and returned to baseline within 4-8 h in both species regardless of the dose of APM. Mean PHE Cmaxs ranged from 73.6 to 1,161 nmol/ml in the rat, and from 78.6 to 1,967 nmol/ml in the mouse. TYR Cmaxs ranged from 91.6 to 502 nmol/ml and from 89.2 to 792 nmol/ml in the rat and mouse, respectively. AUCs and Cmaxs were linear with dose in both species. Peak plasma PHE/LNAA ratios ranged from 0.112 to 1.117 in rats and from 0.121 to 1.769 in mice. Comparison of these ratios with those observed previously in humans indicates that rodents require a 2-6 times higher dose of APM than humans to produce similar increases in plasma PHE/LNAA ratios.

The chronic toxicity of bromovinyldeoxyuridine in beagle dogs.

Bromovinyldeoxyuridine (BVDU), a substituted pyrimidine analog with antiviral activity, was given orally to beagle dogs (6/sex/dosage) at dosages of 0, 5, 12, and 30 mg/kg/day for 52 weeks. Complete physical examinations, including ECG recordings and rectal temperature measurements, and clinical laboratory determinations were performed every 13 weeks. At the end of the dosing period, 4 dogs/sex/dosage were sacrificed and complete gross and microscopic examinations performed. The remaining 2 dogs/sex/dosage were sacrificed following a 13-week recovery period. BVDU had no effect on feed consumption, respiration, body temperature, or heart rate. At 30 mg/kg, males gained less weight than controls. At 12 mg/kg (males) and 30 mg/kg (both sexes) there were slight, but statistically significant decreases in mean corpuscular volume, but no changes in red blood cell (RBC) count, hematocrit, or hemoglobin, and no evidence of reticulocytosis. In males dosed at 30 mg/kg, during the last 6 months of dosing, partial thromboplastin times, serum alanine aminotransferase, and alkaline phosphatase increased, and cholesterol decreased. Histologically, bile ductule hyperplasia and gall bladder epithelial hyperplasia were present at 12 and 30 mg/kg in both sexes at the end of both the dosing and recovery periods. At 30 mg/kg, bone marrow hypocellularity and testicular germ cell atrophy were also present in males. Thus, the liver and gall bladder are the major target organs of chronically administered BVDU in dogs. BVDU causes degenerative and proliferative hepatobiliary damage, and secondarily causes changes in clinical chemical parameters. At higher dosages, there are hypoplastic and degenerative changes in the bone marrow and testes.

Electrocardiogram of the clinically normal, ketamine-sedated Macaca fascicularis.

Electrocardiograms were obtained from 100 clinically normal cynomolgus macaques (Macaca fascicularis) sedated with ketamine hydrochloride. Calculations were made for heart rates and mean electrical axes (frontal, sagittal, and transverse planes) as well as for amplitudes and/or intervals for P, PR, QRS, Q, R, S, and QT. Proposed ECG reference ranges are set forth for this species.

Toxicity studies on the radioprotective agent WR-2721 in CDF1 mice and beagle dogs.

WR-2721, S-2-(3-aminopropylamino)ethylphosphorothioic acid, is used extensively to protect normal cells during the irradiation of neoplastic cells. Dose levels for human radiotherapy are based on results obtained from laboratory animal lethality and toxicity studies. WR-2721 was administered intravenously to CDF1 mice and beagle dogs. Single dose lethality studies in mice showed the average 1/10 of the lethal dose, the median lethal dose and 9/10 the lethal dose to be 508 (1523 mg/m2), 589 (1766 mg/m2), and 682 mg/kg (2047 mg/m2), respectively. The lethal dose for female mice was lower than that for males. The 1/10 lethal dose in mice was slightly toxic to dogs; 1/10 of that dose was nontoxic. The lethal dose for dogs (6000 mg/m2) was higher than that for mice (2000 mg/m2). Clinical signs of toxicosis in the single-dose mouse toxicity study were evident in the 1st week following treatment and declined during the recovery period; signs of toxicosis were transient in dogs. Acute drug-induced pathologic changes included elevated BUN and SGOT levels, lymphoid necrosis, and renal tubular degeneration in mice. These changes were evident in the 1st week following treatment, but had dissipated by study termination. Generalized vascular changes (congestion, hemorrhage, and edema) and renal tubular degeneration occurred in treated dogs that had died or were killed moribund 7 days postinjection. These findings indicate sex-dependent and interspecies variation in the toxicity of WR-2721 with acute, but reversible, pathologic changes.