Preclinical toxicology of zidovudine. An overview

The toxicologic potential of zidovudine (azidothymidine) has been extensively investigated in several species. In rats and mice, the median lethal dose was greater than 750 mg/kg intravenously and greater than 3,000 mg/kg orally. In subacute intravenous toxicity studies, no significant toxicologic alterations were seen in rats or dogs. In cynomolgus monkeys, which as in humans rapidly and extensively glucuronidate zidovudine, a reversible, dose-related, macrocytic anemia was seen in animals given 35, 100, or 300 mg/kg per day for three or six months. In three-month and six-month oral toxicity studies in rats, treatment-related alterations consisted of a mild increase in glucose level in the blood in female rats in both studies and a reversible, slight-to-mild macrocytic anemia in the six-month study. There was no evidence of teratogenicity in rats or rabbits given the drug during gestation. Results for zidovudine were negative in a bacterial mutagenicity assay, but the drug was weakly mutagenic at concentrations of 1,000 to 5,000 micrograms/ml in mammalian cells. Zidovudine caused chromosomal aberrations in cultured human lymphocytes at concentrations of 3 micrograms/ml and higher and had positive results in a cell transformation assay at concentrations of 0.5 micrograms/ml and higher. No bone marrow chromosomal alterations were noted in a cytogenetics study in rats given zidovudine at several intravenous dose levels up to 300 mg/kg.