STUDIES ON THE RELATIONSHIP OF METABOLIC FATE AND HORMONAL EFFECTS OF D,L-METHADONE TO THE DEVELOPMENT OF DRUG TOLERANCE

No appreciable difference in D,L-methadone levels was observed in the tissues of normal and tolerant rats following administration of the compound. Liver slices from tolerant rats were found to metabolize D,L-methadone slightly less rapidly than those from normals. The urinary excretion of the compound in normal and in tolerant animals did not differ greatly but tolerant animals excreted a greater amount of a metabolic product of D,L-methadone. Muscle homogenate from tolerant animals bound D,L-methadone approximately to the same extent as that from normals. Adrenal hypertrophy and perhaps a slight decrease in thyroid activity were observed to accompany the development of tolerance to D,L-methadone. The possible relationships of these factors have been discussed.