Physiological disposition and biotransformation of l-alpha-[2-3H]acetylmethadol (LAAM) in acutely and chronically treated monkeys
Misra, A.L.; Mulé, S.J.; Bloch, R.; Bates, T.R.
Journal of Pharmacology and Experimental Therapeutics 206(2): 475-491
1978
ISSN/ISBN: 0022-3565 PMID: 98628 Document Number: 130500
L-.alpha.-[2-3H]acetylmethadol was previously shown to suppress narcotic withdrawal symptoms effectively in morphine-dependent human subjects. After a 2 mg/kg oral dose of [3H]LAAM t1/2 [half-life] values of LAAM in plasma of acutely and chronically treated monkeys [Macaca mulatta] were 6.9 and 10.5 h, respectively. LAAM disappeared from plasma by 48 h after an acute dose and did not accumulate after chronic administration. Peak plasma levels of acetylnormethadol (AN) in chronically treated monkeys were comparatively higher and declined more rapidly as compared to the acute values. The high peak plasma levels of acetylbisnormethadol (ABNM) in chronically treated monkeys were sustained for prolonged time periods. Enterohepatic circulation of LAAM and metabolites may be responsible for maintaining persistent levels of these compounds in plasma. The percent binding (mean .+-. SE of the mean) of LAAM and ANM with monkey plasma proteins was 79.20 .+-. 3.05 and 66.00 .+-. 0.29, respectively, and the blood/plasma ratio of LAAM was 1.096 .+-. 0.055. Higher levels of LAAM and ANM occurred in the CNS, liver, lung and kidney of chronically treated animals at 6 h after a 2 mg/kg oral dose of LAAM as compared to the acute animals. LAAM was more rapidly cleared from the CNS in the chronic group. The persistence of low levels of ABNM and p-OH-ABNM for prolonged periods in the CNS might play an important role in the long duration of action of LAAM. In acutely and chronically treated animals the percent doses excreted in urine were 1.2 and 2.0 (LAAM), 1.5 and 4.8 (ANM) and 1.5 and 2.4 (ABNM), respectively. Total radioactivity levels in urine and feces were 50% acute and 72% chronic. N-Demethylation, O-deactylation, p-hydroxylation, glucuronide conjugation of hydroxylated compounds. N-acetylation of bisnormethadol and normethadol were the metabolic pathways for LAAM in the acute group. Formation of inactive pyrroline and p-OH-pyrroline metabolites occurred in the chronic group. After a 2 mg/kg i.v. injection of [3H]LAAM, the plasma t1/2.alpha. and t1/2.beta. were 0.84 and 6.8 h, respectively. The mean volume of the central compartment Vc was 4.48 l/kg, mean apparent volume of distribution Vd.beta. was 18.2 l/kg, renal clearance was 0.53 ml/min per kg and systemic availability was 57% of oral dose. LAAM (0.55-1.95% of dose) was excreted free in urine after i.v. injection and major exretion of LAAM and metabolites occurred in feces. Total radioactivity values in urine and feces after single i.v. and s.c. injections were 50-58 and 53-62% of dose, respectively. Chronic LAAM administration enhanced its metabolism and elimination of its metabolites.