Natural (-)- and unnatural (+)-enantiomers of morphine: comparative metabolism and effect of morphine and phenobarbital treatment.

The comparative metabolism of the natural (-)- and the unnatural (+)-morphine was studied in liver microsomes from phenobarbital-treated, morphine-treated and control rats. (-)-Morphine was glucuronidated only at position 3 with the formation of (-)-morphine-3-glucuronide [(-)-M3G] at an average rate of 2.19 nmol X mg protein-1 X min-1. In contrast, (+)-morphine was conjugated preferentially at position 6. The rate of formation of (+)-morphine-6-glucuronide [(+)-M6G] was 3.1 times higher than that of (+)-M3G (0.92 and 0.30 nmol X mg protein-1 X min-1, respectively). Natural morphine was N-demethylated at an average rate of 0.42 nmol X mg protein-1 X min-1, and this rate of N-demethylation was about twice as high as that of (+)-morphine (0.17 nmol X mg protein-1 X min-1). Phenobarbital treatment led to a 3- to 4-fold increase in the formation rate of (-)-M3G and (+)-M6G whereas the glucuronidation of (+)-morphine at position 3 was increased only marginally. No change in the N-demethylation of either enantiomer was observed. In contrast, pretreatment with (-)-morphine decreased the N-demethylation of both enantiomers by about 80% without any effect on the glucuronidation. The increased ratio of the rate of (+)-M6G/(+)-M3G formation after phenobarbital treatment indicates that different isozymes may be involved in the two reactions. This study demonstrates that there is an inherent substrate stereoselectivity and site selectivity for morphine in the rat hepatic uridine 5'-diphosphate-glucuronyltransferase although not as critical as for the opiate receptors mediating analgesia.