Saliva-catalyzed hydrolysis of a ketobemidone ester prodrug: Factors influencing human salivary esterase activity

Abstract Saliva enzyme-catalysed hydrolysis of ester prodrugs containing sensitive ester groups may be a limiting factor to the buccal absorption of such compounds. Using the isopropyl carbonate ester of ketobemidone as a model substance of a hydrolysis-sensitive prodrug the esterase activity of human saliva has been characterized as a function of various factors. The esterase activity was found to decrease rapidly upon storage of the saliva at 37°C. The activity increased with increasing pH in the range 4.5–7.4 and with increasing salivation flow rate up to a rate of 0.9 ml min −1 . Under resting conditions, the flow rate was about 0.2 ml min −1 which implied a greatly decreased esterase activity. The activity was highest after fasting and decreased after intake of a meal. The intraindividual variation in the saliva esterase activity was small whereas a larger interindividual variation was found.