Stereoselective binding of propranolol to human plasma, α1-acid glycoprotein, and albumin

Abstract

Possible stereoselectivity in the plasma binding of propranolol [an antihypertensive agent] was determined. Equilibrium dialysis with plasma from 7 healthy subjects and a deuterium-labeled pseudoracemate of propranolol was used. Plasma binding of the propranolol enantiomers differed with the unbound fraction of (-)-propranolol (22 .+-. 2%: mean .+-. SE) being smaller than that of (+)-propranolol (25.3 .+-. 1.9%). The (-)/(+)-propranolol ratio for the unbound fraction, a measure of the stereoselectivity, was 0.86 .+-. 0.02. There was an inverse correlation between the unbound (-)/(+)-propranolol ratio in individual subjects and overall binding of (.+-.)-propranolol, indicating greater stereoselectivity at high total binding. To assess the site of the stereoselective binding to plasma proteins, the binding of (+)- and (-)-propranolol to human .alpha.1-acid glycoprotein (AGP) and human serum albumin (HSA) was examined. The binding to AGP was stereoselective for (-)-propranolol with a (-)/(+)-propranolol ratio for the unbound fraction of 0.79 .+-. 0.01, whereas, (+)-propranolol was bound to a greater extent to HSA with a (-)/(+)-propranolol ratio for the unbound fraction of 1.07 .+-. 0.01. Although these results demonstrate opposite stereoseselectivity in the binding of (+)- and (-)-propranolol to AGP and HSA, the stereoselective binding of (-)-propranolol to AGP predominates in plasma. This stereoselective plasma binding of the (-)-enantiomer of propranolol could limit the access of this more active enantiomer to .beta.-receptors or other active sites. The uptake of propranolol by red blood. cells was not stereoselective.