TOXICOLOGICAL EVALUATION OF MU-AGONISTS .2. ASSESSMENT OF TOXICITY FOLLOWING 30 DAYS OF REPEATED ORAL DOSING OF MALE AND FEMALE RATS WITH LEVO-ALPHA-NORACETYLMETHADOL HCL (NORLAAM)

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 d ependence. After acute and 7-day pilot studies to define dose levels a ppropriate for use in longer term evaluations, Sprague-Dawley Fats (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-re lated effects included dose-dependent CNS depression paralleled by cha nges in food consumption, body weight gain and fecal output, as well a s reddish urine and abdominal staining. Tolerance developed by day 7. The spectrum of activity observed differed from the parent compound pr imarily in its time course. Cage-biting and gnawing behavior were obse rved only with NorLAAM. Mortality was dose-dependent, with deaths occu rring 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 t o the control range following recovery. Increases in brain/body weight and testes/body weight ratios and decreases in kidney/brain, liver/br ain, spleen/brain and heart/brain ratios, as well as decreases in kidn ey, Liver, spleen and heart absolute weights, achieved statistical sig nificance only for males. At terminal sacrifice, histological findings in the kidneys included increased incidences of tubular mineral depos ition in mid- and high-dose groups of bath sexes and of corticomedulla ry mineral deposition in females. Hepatic centrilobular hypertrophy wa s evident in male and female mid- and high-dose groups. Histopathologi cal changes abated following the recovery period. In summary, acute an d repeated administration of NorLAAM produced a pharmacodynamic profil e commensurate with its role as the primary N-demethylated metabolite of LAAM, which is more potent and less lipophilic than the parent comp ound; this was reflected in the toxicological outcomes observed. Like LAAM, NorLAAM's overall pattern of activity is consistent with its act ivity as a mu-agonist, which stimulates hepatic microsomal enzymes in rodents.