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Influence of endotoxin on the stereoselective pharmacokinetics of oxprenolol, propranolol, and verapamil in the rat
Author(s) -
Laethem Martine E.,
Belpaire Frans M.,
Wijnant Pascal,
Rosseel MarieThérèse,
Bogaert Marc G.
Publication year - 1994
Publication title -
chirality
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.43
H-Index - 77
eISSN - 1520-636X
pISSN - 0899-0042
DOI - 10.1002/chir.530060508
Subject(s) - oxprenolol , chemistry , propranolol , verapamil , enantiomer , pharmacokinetics , pharmacology , stereoselectivity , enantioselective synthesis , stereochemistry , endocrinology , biochemistry , calcium , medicine , organic chemistry , catalysis
The influence of endotoxin‐induced inflammation on the enantioselective pharmacokinetics of propranolol, oxprenolol, and verapamil, which bind to α 1 ‐acid glycoprotein, was studied in the rat. The racemic mixtures were given orally. In the control animals, for propranolol and oxprenolol, the plasma concentrations of the (R)‐enantiomer were higher than those of the (S)‐enantiomer, while for verapamil the reverse was true. Protein binding and intrinsic clearance are the main factors responsible for this enantioselectivity. After endotoxin treatment, for the three drugs tested the plasma concentrations and the plasma binding of both enantiomers were significantly increased. This effect was more pronounced for (R)‐propranolol, (R)‐oxprenolol, and (S)‐verapamil than for their respective antipodes. The enantioselective effect of endotoxin on the plasma concentrations of the drugs studied seems mainly due to the enantioselective increase in binding to α 1 ‐acid glycoprotein. © 1994 Wiley‐Liss, Inc.