FUNDAMENTAL AND APPLIED TOXICOLOGY 8, 5 1- 5 8 (1987) Evaluation of the Teratogenicity and Pharmacokinetics of Diflunisal in Cynomolgus Monkeys

cokinetics and potential teratogenicity of the nonsteroidal antiinflammatory drug, diflunisal, in cynomolgus monkeys. Pregnant cynomolgus monkeys were administered 0.5 % methyl cellu-lose, 20 mg/kg/day diflunisal, or 80 mg/kg/day diflunisal on Days 25 to 48 of gestation. There was no evidence of maternal toxicity, increased abortion rate, fetal growth retardation, or mal-formation. These data demonstrate that diflunisal is not teratogenic in cynomolgus monkeys over a dosage range of 20 to 80 mg/kg/day. Peak plasma levels of diflunisal were found 1 hr after oral administration of [14C]diflunisal at a dosage of 60 mg/kg and declined to low levels by 24 hr. The plasma elimination half-life was calculated to be 10.2 hr over the period of 1 to 8 hr postadministration. Intact diflunisal accounted for 96.4 % of total plasma radioactivity at 0.5 hr and declined to a value of 74 % at 8 hr. Plasma protein binding averaged greater than 99 % over a concentration range of 62.5 to 250 /ig/ml. Urinary excretion of diflunisal and metabolites averaged 66.5 % of the dosage over the first 4 days postadministration, compared with 0.8 % in the feces. The majority of activity represented conjugates of diflunisal. Embryo concentrations of diflunisal on Days 35 to 37 of gestation were 0.7 and 1.1 % of maternal plasma level at 4 h