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The difference in activity between (+)‐ and (‐)‐methadone is intrinsic and not due to a difference in metabolism

The disposition and metabolism of (+)‐ and (‐)‐methadone has been compared in rats. At equal molecular doses, somewhat higher plasma levels of (‐)‐isomer were observed. At equal analgesic doses, brain and plasma concentrations of (+)‐methadone were at least 25 times greater than those of (‐)‐methadone. No qualitative differences were observed between isomers with respect to in vivo metabolic pattern or in vitro N‐demethylation rates. The results strongly support the conclusion that the large differences in analgesic potency between the isomers is due to an intrinsic difference in pharmacologic properties and is not related to a difference in disposition or metabolism.