NONCLINICAL TOXICOLOGY STUDIES WITH ZIDOVUDINE - GENETIC TOXICITY TESTS AND CARCINOGENICITY BIOASSAYS IN MICE AND RATS

Zidovudine (ZDV), an antiviral drug active in the treatment of obtaine d only at the highest concentrations tested (4000 to 5000 mu g/ml) in the absence of metabolic activation. In the presence of metabolic acti vation, the drug was weakly mutagenic at concentrations of 1000 mu g/m l and higher. Following 24 hr treatment in the absence of metabolic ac tivation, ZDV was moderately mutagenic at concentrations up to 600 mu g/ml; dose-related structural chromosomal alterations were seen at. co ncentrations of 3 mu g/ml and higher in cultured human lymphocytes. Su ch effects were not noted at the two lowest concentrations tested, 0.3 and 1 mu g/ml, and BALB/c-3T3 cells were transformed at concentration s of 0.5 mu g/ml and higher. No effects were seen in the Ames Salmonel la plate incorporation and preincubation modification assays (possibly due to bacteriocidal activity of ZDV at low concentrations) at concen trations ranging from 0.01 to 10 mu g/plate or in a single-dose intrav enous bone marrow cytogenetic assay in CD rats. In multidose micronucl eus studies, increases in micronucleated erythrocytes were seen in mic e at doses of 100 to 1000 mg/kg/day, Similar results were seen in rats and mice after 4 or 7 clays of dosing at 500 mg/kg/day. In carcinogen icity bioassays, adjusted doses of 20, 30, or 40 mg/kg/day and 80, 220 , and 300 mg/kg/day were given to CD-1 mice and CD rats, respectively, for up to 22 months in mice and 24 months in rats. ZDV caused a macro cytic, normochromic anemia in both species. No evidence of carcinogeni city was seen in male mice or rats. In female mice, five malignant and two benign vaginal epithelial neoplasms occurred in animals given 40 mg/kg/day. A single benign vaginal epithelial tumor was seen in a mous e given 30 mg/kg/day. In rats, two malignant vaginal epithelial neopla sms were seen in animals given 300 mg/kg/day. In a 7-day study in mice , ZDV was shown to be devoid of estrogenic activity. In an oral pharma cokinetics study, the. AUC was 17 and 140 mu g/ml . hr in female mice and rats given 40 or 300 mg/kg of ZDV, respectively. In contrast, the average steady-state concentration in humans at the recommended daily dose is 0.62 mu g/ml. Twenty-four hour urine concentrations were 1245 and 4417 mu g/ml in female mice and rats given 40 or 300 mg/kg of ZDV, respectively. These values were approximately 26- and 136-fold higher than the human urine concentration at the recommended daily dose. In a one- to three-day study with intravenously administered sodium fluor oscein in rats and mice, retrograde how of urine into the vagina was d emonstrated, In a subsequent lifetime carcinogenicity bioassay in mice in which ZDV was given intravaginally at concentrations of 5 or 20 mg ZDV/ml in saline, 13 vaginal squamous cell carcinomas were seen at th e highest concentration tested. It was concluded that the vaginal tumo rs seen in the oral carcinogenicity studies were the result of chronic local exposure of the vaginal epithelium to high urine concentrations of ZDV. (C) 1996 Society of Toxicology