In vivo carcinogenesis assay of DL-methadone.HCl in rodents.
The extensive clinical use of methadone encouraged the performance of a carcinogenesis bioassay to support risk assessment in man. An oral LD50 of 178 mg/kg was obtained in B6C3F1 mice. Physiologic changes induced by mean oral doses of 15, 30, and 60 mg/kg for 90 days included dose-related central nervous system (CNS) stimulation, fighting, tolerance development, sex-related alteration of food consumption, and no drug-related pathology. In the chronic study dosages were 15 and 60 mg/kg for mice, 16 and 28 mg/kg for male rats, and 46 and 88 mg/kg for female rats. Survival incidences for treated and control rodents were 72-86% for mice and 80-90% for rats. Deaths related to morphologic changes of aging occurred in all groups. CNS stimulation and fighting were more common to male rodents. Growth rates were unchanged for mice but a dose-related inhibition occurred for rats. Higher doses stimulated food intake in both species. Neither the type nor incidence of neoplasia was drug related but a few nonneoplastic lesions may have been. Preliminary plasma methadone levels at necropsy were dose related in the rat.
Rosenkrantz
H
H
Department of Biochemical Pharmacology, EG&G Mason Research Institute, Worcester, Massachusetts 01608.
Fleischman
R W
RW
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D015197:Carcinogenicity Tests; D004435:Eating / Q000187:drug effects; D005260:Female; D007928:Lethal Dose 50; D008297:Male; D008691:Methadone / Q000032:analysis / Q000633:toxicity*; D051379:Mice; D009369:Neoplasms / Q000139:chemically induced*; D051381:Rats; D011916:Rats, Inbred F344
D008691:Methadone