INFLUENCE OF ENDOTOXIN ON THE STEREOSELECTIVE PHARMACOKINETICS OF OXPRENOLOL, PROPRANOLOL, AND VERAPAMIL IN THE RAT

The influence of endotoxin-induced inflammation on the enantioselectiv e pharmacokinetics of propranolol, oxprenolol, and verapamil, which bi nd to alpha1-acid glycoprotein, was studied in the rat. The racemic mi xtures were given orally. In the control animals, for propranolol and oxprenolol, the plasma concentrations of the (R)-enantiomer were highe r than those of the (S)-enantiomer, while for verapamil the reverse wa s true. Protein binding and intrinsic clearance are the main factors r esponsible for this enantioselectivity. After endotoxin treatment, for the three drugs tested the plasma concentrations and the plasma bindi ng of both enantiomers were significantly increased. This effect was m ore pronounced for (R)-propranolol, (R)-oxprenolol, and (S)-verapamil than for their respective antipodes. The enantioselective effect of en dotoxin on the plasma concentrations of the drugs studied seems mainly due to the enantioselective increase in binding to alpha1-acid glycop rotein. (C) 1994 Wiley-Liss, Inc.