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Abstract
1. Following a subcutaneous dose (4 mg/kg) of [3H]methadone, peak levels of drug occurred in plasma, tissues and selected areas of the central nervous system (CNS) 2 h after injection in both non-tolerant and tolerant dogs. Highest concentrations of methadone were attained in bile and lung compared to other tissues.
2. Levels of methadone in plasma, tissue and CNS of tolerant and non-tolerant animals were not markedly different up to 8 h after injection, but a much faster rate of egression of free drug (lower t1/2) was observed subsequently in tolerant dogs.
3. Peak levels of methadone in various areas of the CNS ranged between 2·7 (spinal cord) to 3·6 (thalamus) μg/g in non-tolerant and 3·0 (cerebellum) to 4·1 (thalamus) μg/g in tolerant dogs 2 h after injection. No marked accumulation of methadone occurred in selected areas of the CNS in spite of the persistence of drug in these areas.
4. The plasma protein electrophoretic profiles did not differ between control, non-tolerant and tolerant dogs.
5. Similar qualitative patterns of metabolites were observed in non-tolerant and tolerant dogs and the development of tolerance did not appear to modify the metabolic pathways of methadone.