STEREOSELECTIVE HYDROLYSIS OF O-ISOVALERYL PROPRANOLOL AND ITS INFLUENCE ON THE CLEARANCE OF PROPRANOLOL AFTER ORAL-ADMINISTRATION

The stereoselective hydrolysis of O-isovaleryl propranolol (isovaleryl-PL) was studied using phosphate and Tris-HCl buffers (pH 7.4), dog plasma, and liver preparations. The 10000g supernatant, microsomes, and cytosol were prepared from the liver homogenate. The hydrolysis rate of isovarelyl-PL was accelerated in the order Tris buffer < plasma = phosphate buffer << 10000g supernatant of liver = river cytosol < liver microsomes. The high plasma protein binding of the prodrug brought about the extremely slow hydrolysis rate of isovaleryl-PL in plasma. No difference was observed in the hydrolysis rate between the isomers of isovaleryl-PL in buffers. The hydrolysis rate was 2-3 times faster with the (R)-isomer than with the (S)-isomer using racemate in dog plasma and liver preparations. The hydrolysis of each enantiomer was inhibited by the other enantiomer. For hydrolysis in microsomes the K-m values of (R)- and (S)-isomers were same, and the V-max of the (R)-isomer was 3 times greater than that of the (S)-isomer. These data suggested the mutual interaction of (R)- and (S)-isomers during the hydrolysis process and the rapid hydrolysis of isovaleryl-PL in liver after absorption. The AUC of PL enantiomers after oral administration of racemic isovaleryl-PL was about 2 times higher compared to 2 mg/kg equivalent molar dose of racemic PL in beagle dogs, and the corresponding plasma levels were not stereoselective from both PL and prodrug. The amount of (R)-PL absorbed after administration of a 5 mg/kg dose of racemic PL was 2-fold greater than (S)-PL, because of the stereoselective oxidation and glucronidation of (S)-PL. The total AUC of (S)- and (R)-PLs after PL administration at a 5 mg/kg dose was equivalent to the total AUC of PL from a 2 mg/kg equivalent molar dose of racemic isovaleryl-PL. The absorption rates of PL enantiomers after isovaleryl-PL administration were significantly greater than those after PL administration at both 2 and 5 mg/kg dose. The plasma levers of PL after oral administration were increased by the prodrug through rapid absorption. Furthermore, the slower hydrolysis rate of the (S)-isomer of isovaleryl-PL may be a factor in the lower first-pass clearance of (S)-PL.