BIOACTIVATION OF MORPHINE-3-PROPIONATE, A PRODRUG OF MORPHINE, IN TISSUES FROM DIFFERENT SPECIES

The bioactivation of the morphine prodrug, morphine-3-propionate, has been evaluated by determination of the first-order hydrolysis rate in different tissue homogenates and blood fractions from various mammal s pecies, including man. The hydrolysis rates were determined in whole b lood, serum and plasma from rat, rabbit and man, in serum from pig, in liver, kidney, brain, buccal mucosa, muscle and skin homogenate from rat, rabbit and pig and in skin homogenate from man. Within the same s pecies there was no difference in the enzymatic activity in whole bloo d, serum and plasma. Comparing the enzymatic activity in blood fractio ns from the various species, the activity was higher in man followed b y rabbit, rat and pig, respectively. The enzymatic activity in the tis sue homogenates was general highest in liver followed by kidney, brain , buccal mucosa, muscle and skin. The tissue homogenate from rabbit ha d higher enzymatic activity than those from rat, which again showed hi gher activity than those from pig. Comparison of the Michaelis-Menten parameters, K-m and V-max, obtained using pig and rat serum respective ly, suggested that morphine-3-propionate has a lower affinity for enzy mes present in pig serum than in rat serum and that the enzymes found in pig serum has a lower hydrolytic capacity than those in rat serum. The results obtained in this study indicate that the three animal spec ies investigated, can serve as a model for man in bioactivation studie s on morphine-3-propionate and possibly for other short chain morphine -3-esters as well. (C) 1997 Elsevier Science B.V.