As part of studies aiming at developing a ketobemidone prodrug suitable for buccal or sublingual administration, the potential impact of saliva enzyme-catalyzed hydrolysis of various ester prodrugs was assessed. The hydrolysis of three ketobemidone esters in human whole saliva, obtained under conditions ensuring maximal esterase activity, was studied as a function of ester concentration at 37°C. The kinetics of hydrolysis could be accounted for in terms of the Michaelis-Menten equation and the rate parameters K(m) and V(max) were determined. Due to the occurrence of zero-order kinetics at pharmacologically relevant prodrug concentrations, degradation of the esters by saliva enzymes was predicted to occur to only a minor extent (1-6%) under conditions similar to those prevailing in vivo after administration of buccal or sublingual tablets of the esters. The mode of administration of tablets for use in the mouth and their rate of disintegration were shown to have some influence on the rate of saliva secretion and hence on saliva esterase activity but not to an extent compromising the efficient buccal or sublingual delivery of the ketobemidone prodrugs.