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 p ropranolol (butyryl PL) in rat liver microsomes and plasma involves carboxy lesterase. The hydrolysis of (S)-butyryl PL in plasma was specifically inhi bited 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 s tereoselectivity 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 anti body against a high affinity carboxylesterase (hydrolase A, RH1). Moreover, the high Km value and the high IC50 for phenylmethylsulfonyl fluoride (PMS F) against the hydrolysis of butyryl PL in rat liver microsomes suggest tha t a low affinity carboxylesterase (perhaps hydrolase B) might be involved i n this hydrolysis in rat liver. Chirality 11:10-13, 1999. (C) 1999 Wiley-Li ss, Inc.