EFFECTS OF THE ESTER MOIETY ON STEREOSELECTIVE HYDROLYSIS OF SEVERAL PROPRANOLOL PRODRUGS IN RAT-TISSUES

The stereochemical characteristics of the hydrolysis of several ester- type prodrugs of propranolol, O-acetyl, O-propionyl, O-butyryl, O-piva loyl and succinyl esters, were studied in phosphate buffer (pH 7.4), r at plasma and rat tissue homogenates. In phosphate buffer, no differen ces were observed in the hydrolysis rate between the esters of (R)- an d (S)-propranolol. The effects of the ester moieties on the hydrolysis rate in phosphate buffer were in the following order: acetate > propi onate > butyrate > succinate > pivalate. In rat plasma and tissue homo genates, the hydrolysis of the esters was accelerated, and stereoselec tive hydrolysis was observed. In plasma, the hydrolysis of the (R)-iso mer was faster than that of the (S)-isomer except for the succinate es ter. On the other hand, in the liver and intestine homogenates, the (S )-isomer was hydrolyzed faster than the (R)-isomer except for the succ inate and pivalate esters in the liver homogenate. Also, the ratio of the hydrolysis rates (S/R) changed with the type of prodrug. As the le ngth of the alkyl chain of the ester increased, the S/R ratio approach ed unity in liver and intestine homogenates but stayed almost constant in plasma. For the pivalate ester, stereoselective hydrolysis was obs erved in plasma and intestine homogenate but not in liver homogenate. The stereoselective hydrolysis of the succinate ester was observed onl y in intestine homogenate, but the S/R ratio was almost 1 in plasma, l iver and intestine homogenates. No interconversion between (R)- and (S )-isomer was observed during the hydrolysis of any of the ester prodru gs. These results indicate that hydrolysis of ester-type prodrugs of p ropranolol occurs stereoselectively in rat tissues, and that its selec tivity is dependent on the kind of tissue and prodrug.