Stereoselective oral bioavailability of (+/-)-propranolol in the dog. A GC-MS study using a stable isotope technique

The disposition of (+)- and (-)-propranolol and their glucuronic acid conjugates, (+)-POG and (-)-POG, in plasma was determined in 5 dogs following single 160 mg oral doses of stable isotope labeled racemic propranolol. Each animal received one dose of the racemate with the (+)-isomer labeled with two deuteriums and one dose with the (-)-isomer labeled. The isomers were separated and measured by gas chromatography-mass spectrometry. No stable isotope effect was detected. The area under the plasma concentration - time curve (AUC) for (-)-propranolol was only 54 +/- 10 per cent (mean +/- SD; n = 10) of the AUC for (+)-propranolol. The AUC of (-)-POG exceeded the AUC of (+)-POG by 4.02 +/- 1.22 times (mean +/- SD: n = 10). The time to peak plasma concentration (3.9-4.3 hr) and the half-life (1.6-1.9 hr) were identical for both isomers of propranolol as well as of POG. These results demonstrate a significantly lower oral bioavailability of (-)- as compared to (+)-propranolol in the dog, which appears to be associated with stereoselective presystemic glucuronidation of (-)-propranolol.