RESUMO
Turpentine oil treatment (0.2 mL kg-1, s.c.) was used to increase the plasma concentration of alpha 1-acid glycoprotein (0.13 mg mL-1 in control rats) to 1.72 mg mL-1 after 2 days, and allow assessment of its effects on the pharmacokinetics and stereoselective binding of three beta-blockers. Racemates (5 mg kg-1) were administered intravenously to control and turpentine oil-pretreated rats and the plasma concentrations were determined up to 90 min. Stereoselective analysis showed the apparent distribution volume and the area under plasma concentration-time curves (AUC) of R-(+)-propranolol to be, respectively, one-quarter and twice those of the S-(-)-enantiomer and differences in pharmacokinetic parameters between the two were magnified by turpentine oil pretreatment. Pharmacokinetic parameters of oxprenolol enantiomers were essentially similar for the controls but after turpentine oil pretreatment, a higher affinity of the R-(+)-enantiomer for plasma was observed. Acebutolol enantiomers behaved non-stereospecifically throughout. These results were consistent with predictions from the in-vitro stereospecific binding properties of these agents to purified rat alpha 1-acid glycoprotein.
Assuntos
Antagonistas Adrenérgicos beta/farmacocinética , Orosomucoide/metabolismo , Terebintina/farmacologia , Acebutolol/metabolismo , Acebutolol/farmacocinética , Animais , Ensaio de Imunoadsorção Enzimática , Azeite de Oliva , Oxprenolol/metabolismo , Oxprenolol/farmacocinética , Óleos de Plantas/administração & dosagem , Propranolol/metabolismo , Propranolol/farmacocinética , Ratos , Estereoisomerismo , Terebintina/administração & dosagemRESUMO
The stereoselectivity of binding of four beta-blockers, pindolol, propranolol, oxprenolol and acebutolol, to purified rat alpha 1-acid glycoprotein (AAG) was examined using equilibrium dialysis. Pindolol and propranolol were bound stereoselectively to AAG, whereas binding of oxprenolol was non-stereospecific. Neither of the enantiomers of acebutolol bound to either AAG or any other plasma protein. The affinity of (+)-pindolol was 25 times that of (-)-pindolol, as determined in a single enantiomer experiment. Both enantiomers of propranolol demonstrated two classes of binding sites in AAG, the total binding for the high affinity site for (+)-propranolol being double that of (-)-propranolol, which could explain the higher binding of the (+)-enantiomer in racemate experiments. These results further showed that stereoselective binding to a rat AAG is not a property common to all beta-blockers.