Metabolic deacetylation: in vitro and in vivo studies in man, rat, dog and rhesus monkey with isomeric tetrahydroisoquinolyl derivatives of 3,4-dimethylbenzyl acetate.

The pharmacological activities of a racemic mixture of tetrahydroisoquinolyl derivatives of 3,4-dimethylbenzyl acetate, (+/-) Ro 03-4661 and the corresponding resolved isomers (+) Ro 03-4661 and (--) Ro 03-4661 have been studied in rat and rhesus monkey. The racemate and the (--) isomer showed narcotic analgesic activity by the oral route in both species. Drug metabolism studies indicated that the activity was probably due to metabolic Deacetylation to the corresponding carbinol Ro 03-4632. deacetylation did not occur in the dog, but was observed in the rat and rhesus monkey. In both these species the hydrolysis was more extensive after oral than parenteral administration. In vitro studies also showed considerable species variation in the ability of blood and tissue esterases to hydrolyse the different stereochemical isomers.