The metabolism and distribution of racemic and optically active prodines (1) and desmethylprodine (2) were investigated in mice. The (+)-antipodes of the analgetically moee active prodines weee demethylated moee slowly in vitro. However, a significant difference between the in vivo rates of decline in plasma was observed only between (3-prodine antipodes. It was found that O -> N propionyl migration of the demethylated compounds (4, 8, 13) proceeds at a rapid rate at pH > 9.5 to yield the corresponding amides (5, 9, 14), and this was utilized as an analytical procedure to quantitate the amount of demethylation. Within 15 min after sc administration each isomer achieved steady-state brain/plasma ratios, suggesting rapid equilibration between these tissues. Ratios of >5 weee attributed to the lipophilic nature of the prodines. The differences in affinities of the prodine isomers for plasma proteins are small. In no case were the differences in analgetic potency accounted for by distribution or metabolism. It is concluded that the large enantiomeric potency ratios for 1 are related primarily to stereoselective events at analgetic receptors.