PHYSIOLOGICAL DISPOSITION AND METABOLISM OF levo-METHADONE-1-³H IN NONTOLERANT AND TOLERANT RATS

¹ New York State Narcotic Addiction Control Commission Testing and Research Laboratory, Brooklyn, New York

A method is described for the estimation of levo-methadone-1-³H in biological materials which has a minimal sensitivity of 1 to 2 ng. After a dose of levo-methadone-1-³H 10 mg/kg s.c., to male Wistar rats, the mean peak levels were 1798 ng/ml in plasma at 0.5 hour and 4502 ng/g in brain at 1 hour, respectively. Measurable quantities of drug persisted in brain (20 ng/g) and other tissues up to three weeks or longer, even though no measurable amounts of drug were present in plasma after 24 hours. Orally administered drug (10 mg/kg) produced levels in plasma and brain approximately 1/25 of those observed after subcutaneous injection. The drug was localized in lung, liver, kidney and brain, with lower concentrations in heart and muscle. The mean percentages of free drug excreted in 96-hour urine and feces after injection of 10 mg/kg s.c. were 11.37 and 14.78, respectively. The total radioactivity values in urine and feces were 19.49% and 29.8%, respectively. After an injection of 10 mg/kg s.c., the concentrations of drug in brain and plasma of tolerant rats were consistently lower than those in nontolerant rats at each time interval. After oral administration of methadone (50 mg/kg), the cencentrations at 0.5 and 1 hour in brain and plasma of tolerant rats were higher and subsequently dropped to values lower than those observed in the nontolerant rats. The approximate half-lives of drug in brain and plasma of nontolerant rats after 10 mg/kg s.c. injection were 2.4 and 3.7 hours, respectively, and in tolerant rats 1.5 and 1.7 hours, respectively. By the oral route (50 mg/kg), half-lives in brain and plasma of nontolerant rats were approximately 14 and >8 hours respectively, and in tolerant rats, 3.1 hours in brain and 1.4 hours in plasma. The rate of disappearance of drug from plasma and brain was faster in the tolerant rats and there was evidence for a faster rate of metabolism of drug in these animals. The drug was extensively metabolized and, in addition to known substituted pyrrolidine, pyrroline and N-oxide metabolites, evidence of six other phenolic glucuronide-conjugated amines was obtained. Four had the characteristics of a phenolic tertiary amine, one a secondary amine and the other a primary amine, respectively. Evidence for the presence of a phenolic primary amine methadone metabolite with structural similarity to norepinephrine was obtained in rat brains at the time of peak analgesia. Later, this metabolite conjugated with protein persisted in brain along with free methadone. These observations, coupled with consistent differences in physiological disposition of methadone in brain and plasma of nontolerant and tolerant rats, may have relevance to the mechanism of pharmacological tolerance and the protracted withdrawal syndrome observed with methadone.

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