Stereoselectivity and Differential Metabolism in vivo of Dextro and Laevo-Methadone-1-³H

Abstract

MORPHINE-LIKE analgesics which exist as two or more optically active enantiomorphs are known to exert their pharmacological action exclusively or preponderantly in one configuration¹. Dextro-isomers are generally inactive with respect to analgesia and effects on respiration and do not produce physical dependence in contrast to the pharmacologically active laevo-enantiomorphs. Optical isomers therefore have potential for the elucidation of basic mechanisms concerned with pharmacological effects. Previous studies on d-and l-isomers of methadone^2–4 (Fig. 1), racemorphan^5–7, zocine⁸, and prodine⁹ have not shown any meaningful delineations in absorption, regional distribution or metabolism of these isomers. Stereoselective events at the hypothetical asymmetric analgesic receptor have generally been postulated as the chief mediator of molecular specificity^10–13. Together with previous work on l-methadone (refs. 14,15 and A. L. M., S. J. M., J. R. Bloch and N. L. Vadlamani, submitted for publication) we show here for the first time that the observed enantiomeric potency differences between d- and l-metha-done-1-³H could be attributed to (1) the formation of an apparently active metabolite in rat brain with l-methadone¹⁴, but not with d-isomer; (2) significant differences in half-lives of these isomers in rat brain and plasma; (3) differential Stereoselective N-dealkylation pathway being a major route of metabolism with l- but not with d-isomer.