Toxicological evaluation of mu-agonists. Part II: Assessment of toxicity following 30 days of repeated oral dosing of male and female rats with levo-alpha-noracetylmethadol HCl (NorLAAM).

Abstract

This study evaluated levo-alpha-noracetylmethadol (NorLAAM), the first N-demethylated metabolite of levo-alpha-acetylmethadol (LAAM), a long-acting morphine-like (mu) agonist, approved in 1993 to treat opiate dependence. After acute and 7-day pilot studies to define dose levels appropriate for use in longer term evaluations, Sprague-Dawley rats (20 of each sex per group) were gavaged with doses of 4.4-25.9 mg kg(-1) day(-1) for 30 days followed by a 14-day recovery period. Treatment-related effects included dose-dependent CNS depression paralleled by changes in food consumption, body weight gain and fecal output, as well as reddish urine and abdominal staining. Tolerance developed by day 7. The spectrum of activity observed differed from the parent compound primarily in its time course. Cage-biting and gnawing behavior were observed only with NorLAAM. Mortality was dose-dependent, with deaths occurring predominantly during the first week. At day 30, all male-treated groups exhibited statistically significant, dose-dependent decreases in body weight gain and increases in serum cholesterol that returned to the control range following recovery. Increases in brain/body weight and testes/body weight ratios and decreases in kidney/brain, liver/brain, spleen/brain and heart/brain ratios, as well as decreases in kidney, liver, spleen and heart absolute weights, achieved statistical significance only for males. At terminal sacrifice, histological findings in the kidneys included increased incidences of tubular mineral deposition in mid- and high-dose groups of both sexes and of corticomedullary mineral deposition in females. Hepatic centrilobular hypertrophy was evident in male and female mid- and high-dose groups. Histopathological changes abated following the recovery period. In summary, acute and repeated administration of NorLAAM produced a pharmacodynamic profile commensurate with its role as the primary N-demethylated metabolite of LAAM, which is more potent and less lipophilic than the parent compound; this was reflected in the toxicological outcomes observed. Like LAAM, NorLAAM's overall pattern of activity is consistent with its activity as a mu-agonist, which stimulates hepatic microsomal enzymes in rodents.