In vivo carcinogenesis assay of L-alpha-acetylmethadol.HCl in rodents.
With increasing clinical use of L-alpha-acetylmethadol.HCl (LAAM), findings of a carcinogenic bioassay could be useful in risk assessment. Initial studies provided a sex-related oral LD50 in B6C3F1 mice, 126 mg/kg for males and 71 mg/kg for females, and changes after treatment with mean doses of 8, 18, and 33 mg/kg for 90 days which included hyperactivity and unchanged growth rate, food intake, and morphology. Twenty-four-month oral doses were 7.6 and 30.1 mg/kg for mice, 3.1 and 9.7 mg/kg for male rats, and 5.7 and 16.6 mg/kg for female rats. LAAM was lethal in high-dose male mice (40% survival) whereas survival rates of 74-78% were similar in other treated and control groups. An 80-90% survival rate was seen for rats. Deaths related to aging and concomitant morphologic changes occurred randomly in all groups. The causes of LAAM-induced deaths were not established. Central nervous system stimulation and fighting were more common to male rodents. A dose-related inhibition of growth was also common but food intake was stimulated in male mice and both sexes of rats. An increase in liver neoplastic nodules was dose related and drug related in rats. Some nonneoplastic lesions may have been drug related. Terminal plasma LAAM and metabolite levels were generally dose related.
Rosenkrantz
H
H
Department of Biochemical Pharmacology, EG&G Mason Research Institute, Worcester, Massachusetts 01608.
Fleischman
R W
RW
D000818:Animals; D015197:Carcinogenicity Tests; D004435:Eating / Q000187:drug effects; D005260:Female; D007928:Lethal Dose 50; D008297:Male; D008691:Methadone / Q000031:analogs & derivatives*; D008692:Methadyl Acetate / Q000378:metabolism / Q000633:toxicity*; D051379:Mice; D008815:Mice, Inbred Strains; D009369:Neoplasms / Q000139:chemically induced*; D051381:Rats; D011916:Rats, Inbred F344
D008692:Methadyl Acetate; D008691:Methadone