Stereoselective Hydrolysis of O‐Isovaleryl Propranolol and Its Influence on the Clearance of Propranolol after Oral Administration

Abstract

The stereoselective hydrolysis ofO‐isovaleryl propranolol (isovaleryl‐PL) was studied using phosphate and Tris‐HCI buffers (pH 7.4), dog plasma, and liver preparations. The 10000gsupernatant, 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 < 10000gsupernatant of liver = liver 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 theKmvalues of (R)‐ and (S)‐isomers were same, and theVmaxof 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 levels 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.