Characterization of esterases involved in the stereoselective hydrolysis of ester-type prodrugs of propranolol in rat liver and plasma.

An inhibition study showed that the stereoselective hydrolysis of butyryl propranolol (butyryl PL) in rat liver microsomes and plasma involves carboxylesterase. The hydrolysis of (S)-butyryl PL in plasma was specifically inhibited by eserine and bis-nitrophenyl phosphate (BNPP), compared to the (R)-isomer, despite the non-stereoselective hydrolysis of butyryl PL in plasma. In addition, inhibition of hydroloysis by eserine and BNPP showed little stereoselectivity for butyryl PL in liver, although liver microsomes showed an (S)-preferential hydrolysis for butyryl PL (R/S ratio of Vmax/Km: 2.1 +/- 0.2). The hydrolysis of butyryl PL was not inhibited by a polyclonal antibody against a high affinity carboxylesterase (hydrolase A, RH1). Moreover, the high Km value and the high IC50 for phenylmethylsulfonyl fluoride (PMSF) against the hydrolysis of butyryl PL in rat liver microsomes suggest that a low affinity carboxylesterase (perhaps hydrolase B) might be involved in this hydrolysis in rat liver.