Summary
The toxicity of AZT/methadone combination therapy was assessed in CD-1 male and female mice at the following doses of AZT/methadone (mg/kg/day):
- 0/0
- 200/0
- 400/0
- 800/0
- 0/5
- 200/5
- 400/5
- 800/5
- 0/15
- 200/15
- 400/15
- 800/15
- 0/30
- 200/30
- 400/30
- 800/30
Parameters evaluated include mortality and clinical observations, body weights, day of preputial separation, day of vaginal opening, estrous cyclicity, gross pathology, organ weights and histopathology.
Male mice (10/group) were dosed on Study Days 5 to 24 and sacrificed on Study Day 26-27. Prior to dosing (Study Days 0-4) the male mice were cohabited with female mice (20/group). The sperm-positive female mice were dosed on Days 6 through 15 of gestation and sacrificed on scheduled Day 4 of lactation. A second group of female mice (20/group) were dosed on Study Day 0 and throughout mating on Study Days 9 to 13 until scheduled sacrifice on Day 18 of gestation. Adult mice were evaluated for clinical signs, body weight, and hematologic parameters. Offspring from each group were evaluated for viability, external anomalies, and weight.
Except for marginal decreases in white blood cell counts (decreases in segmented neutrophils and lymphocytes) in males, no toxicity from methadone administration was observed. AZT (alone or in combination with methadone) induced reproductive/developmental and hematologic toxicity. In males, anemia and leukopenia (decreases in both granulocytic and lymphocytic cell series) were present at all dose levels, and thrombocytosis was present at the high dose level. Epididymal sperm motility was decreased at all dose levels, and epididymal sperm count was increased at the mid-and high-dose levels. In the female(a) groups, neutropenia was observed at all dose levels, and anemia was present in the high-dose group. Developmental toxicity included decreased implantation and litter size and increased resorption at all dose levels. In males, the no-observable-adverse-effect-level (NOAEL) for toxicity was less than 200 mg/kg/day. In females, the approximate NOAEL for both maternal and developmental toxicity was also less than 200 mg/kg/day. The results suggest that coadministration of methadone and AZT does not alter the toxicity of the individual agents. AZT induces developmental toxicity at or below doses that produce hematological toxicity.