Abstract
The stereochemical compositions of D-32, propranolol and their glucuronides in the plasma of dog and rat were determined after a single administration 10-30 mg/kg oral dose of stable isotope labeled pseudoracemates of D-32 and propranolol. The parent drug and glucuronic acid conjugates after enzymatic hydrolysis were analyzed by gas chromatography-mass spectrometry (GC-MS) after trifluoroacetate derivatization. The amounts of these diasteroisomers varied inanimal species, in dog Plasma level (-)-isomer was 2-4 fold higher than its isomer whereas in rat the (-)-isomer was equal to the (+)-enantiomer.
Similar species-related differences were observed in the in vitro formation of the isomeric D-32 glucuronidations. The diastereomeric glucuronidations of (-)-and (+)-enantiomers formed by incubating the racemic drug with animal liver microsomes were also quantitated by GC-MS. The values for the apparent Km on the glucuronidation in dog liver microsomes were 0.87 and 0.63nm, and those of the Vmax. were 11.1 and 1.7nmol/ min/100mg for (-)-and (+)-D-32, respectively. The glucuronidation in the dog and rabbit liver occurred stereoselectively with 3 to 4 fold more (-)-D-32 glucuronide than its isomer, whereas in rat the glucuronidation was less stereoselective. The higher oral bioavailability of (+)-D-32 and (+)-propranolol in dog is suggested to be due to stereoselective presystemic hepatic removal of (-)-propranolol by glucuronidation.
