SALIVA-CATALYZED HYDROLYSIS OF A KETOBEMIDONE ESTER PRODRUG - FACTORS INFLUENCING HUMAN SALIVARY ESTERASE-ACTIVITY

Saliva enzyme-catalysed hydrolysis of ester prodrugs or drugs containing sensitive ester groups may be a limiting factor for 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-degrees-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.