Evaluation of the teratogenicity and pharmacokinetics of diflunisal in cynomolgus monkeys

This study examined the pharmacokinetics and potential teratogenicity of the nonsteroidal antiinflammatory drug, difflunisal, in cynomolgus monkeys. Pregnant cynomolgus monkeys were administered 0.5% methyl cellulose, 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 malformation. 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 μg/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 hr postadministration of 20 or 60 mg/kg, respectively.