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 isovaleryl-PL was accelerated in the order Tris buffer < plasma = phosphate buffer << 10000g supernatant 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 the Km values of (R)- and (S)-isomers were same, and the Vmax 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.(ABSTRACT TRUNCATED AT 250 WORDS)
Shameem
M
M
Faculty of Pharmaceutical Sciences, Kumamoto University, Japan.
Imai
T
T
Yoshigae
Y
Y
Sparreboom
A
A
Otagiri
M
M
D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D004285:Dogs; D006868:Hydrolysis; D008862:Microsomes, Liver / Q000378:metabolism; D011355:Prodrugs / Q000378:metabolism / Q000493:pharmacokinetics*; D011433:Propranolol / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D013237:Stereoisomerism
D011355:Prodrugs; C079647:O-isovaleryl propranolol; D011433:Propranolol