The protein binding of the enantiomers of gallopamil has been investigated in solutions of human serum albumin, a,-acid glycoprotein and serum. Over the range of concentrations attained after oral gallopamil administration, the binding of both enantiomers to albumin, a,-acid glycoprotein, and serum proteins was independent of gallopamil concentration. The binding to both human serum albumin (40 gfiter) [range of fraction bound vb) R 0.624 to 0.699; S: 0.502 to 0.6051 and a,-acid glycoprotein (0.5 ghter) (range offb R 0.530 to 0.718; S: 0.502 to 0.620) was stereoselective, favoring the (Rbenantiomer (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 (f6: 0.943 * 0.016) was lower (P < 0.05) than that of (R)-gallopamil (tb: 0.960 2 0.010). The serum protein binding of both (R)-and ( S ) -g d o p d was unaffected by their optical antipodes v b R 0.963 -+ 0.011; s: 0.948 2 0.015) indicating that at therapeutic concentrations a protein binding enantiomerenantiomer interaction does not occur. The protein binding of (R)-and (3-gallopamil ex vivo 2 h after single dose oral administration of 50 mg pseudoracemic gallopamil v b R: 0.960 2 0.010: predialysis [Rl 6.9 to 35.3 ng/ml; S: 0.943 2 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.