Enantioselective gallopamil protein binding

The protein binding of the enantiomers of gallopamil has been investigated in solutions of human serum albumin, α 1 ‐acid glycoprotein and serum. Over the range of concentrations attained after oral gallopamil administration, the binding of both enantiomers to albumin, α 1 ‐acid glycoprotein, and serum proteins was independent of gallopamil concentration. The binding to both human serum albumin (40 g/liter) [range of fraction bound ( f b ) R: 0.624 to 0.699; S: 0.502 to 0.605] and α 1 ‐acid glycoprotein (0.5 g/liter) (range of f b R: 0.530 to 0.718; S: 0.502 to 0.620) was stereoselective, favoring the (R)‐enantiomer (predialysis gallopamil concentrations 2.5 to 10,000 ng/ml). When the enantiomers (predialysis gallopamil concentration 10 ng/ml) were studied separately in drug‐free serum samples from six healthy volunteers the fraction of (S)‐gallopamil bound ( f b : 0.943 ± 0.016) was lower ( P < 0.05) than that of (R)‐gallopamil ( f b : 0.960 ± 0.010). The serum protein binding of both (R)‐ and (S)‐gallopamil was unaffected by their optical antipodes ( f b R: 0.963 ± 0.011; S: 0.948 ± 0.015) indicating that at therapeutic concentrations a protein binding enantiomer–enantiomer interaction does not occur. The protein binding of (R)‐ and (S)‐gallopamil ex vivo 2 h after single dose oral administration of 50 mg pseudoracemic gallopamil ( f b R: 0.960 ± 0.010: predialysis [R] 6.9 to 35.3 ng/ml; S: 0.943 ± 0.016: predialysis [S] 9.5 to 30.7 ng/ml) was comparable to that observed in vitro in drug‐free serum. Gallopamil metabolites formed during first‐pass following oral administration, therefore, do not influence the protein binding of (R)‐ or (S)‐gallopamil. © 1993 Wiley‐Liss, Inc.