Halothane inhibition of propranolol metabolism is stereoselective

Abstract

Propranolol, like many drugs, is used clinically as a racemic mixture. The major pharmacodynamic effects of propranolol, however, are mediated by the (-)-isomer, which is 100 times as potent as the (+)-isomer. The two isomers also differe in their pharmacokinetic characteristics. To determine whether halothane anesthesia stereoselectively inhibits the metabolism of racemic propranolol, eight male mongrel dogs were studied. On the first day of the study, 40 mg racemic propranolol was infused into the portal vein and arterial blood samples were obtained over the following 4 h for the measurements of (+)- and (-)-propranolol concentrations by HPLC. The study was repeated 24 h later during 2 MAC halothane anesthesia, when the intrinsic clearance of total propranolol was decreased by 67.5 ± 5%, from 6.14 ± 1.1 l/min to 1.84 ± 0.4 l/min (P < 0.05). The decrease in intrinsic clearance was stereoselective, (-)-propranolol being affected to a greater extent than (+)-propranolol; thus, the decrease in the clearance of (-)-propranolol, from 10.96 ± 2.7 l/min to 2.6 ± 0.7 l/min (73 ± 5%) was significantly (P < 0.05) greater than the decrease in the clearance of (+)-propranolol, (62 ± 3%) from 4.3 ± 0.8 l/min to 1.5 ± 0.3 l/min. Furthermore, the ratio of the intrinsic clearance of (-)-propranolol to the intrinsic clearance of (+)-propranolol was significantly (P < 0.05) reduced by halothane anesthesia, from 2.42 ± 0.29 to 1.69 ± 0.11. Stereoselective inhibition of propranolol metabolism results in proportionally higher concentrations of (-)-propranolol during halothane anesthesia than are present in awake dogs. Thus, the pharmacodynamic change will be substantially greater than would have been predicted from the measurement of total propranolol concentrations alone. Since a large number of anesthetic and nonanesthetic drugs are administered as racemates during the perioperative period, stereoselective changes in drug disposition may be a previously undetected factor in the development of toxicity.