The stereoselective binding of six pairs of basic, one pair of acidic drug enantiomers, and one pair of diastereomers for human alpha 1-acid glycoprotein was investigated by means of competition experiments against [3H]propranolol- or [14C]nicardipine-labelled binding sites using equilibrium dialysis to separate free from bound marker ligand. The affinity constants (Ka) for association of [3H]propranolol and [14C]nicardipine with alpha 1-AGP were 1.2 +/- 0.6 X 10(5) M-1 and 3.4 +/- 1.4 X 10(5) M-1, respectively, and control binding amounted to 57 +/- 7 and 91 +/- 2%, respectively. The following selectivity factors, calculated as the ratio of the higher over the lower enantiomer concentrations displacing 15% of control radiomarker binding (IC15-value), were obtained against propranolol and nicardipine: (-)/(+) propranolol: 1.9 and 1.7.; (+)-/(-)-disopyramide: 2.8 and 1.4; (+)-/(-)-verapamil: 1.6 and 1.9; (+)-(S)-/(-)-(R)-202-791, a dihydropyridine derivative: 2.6 and 2.0; (-)-/(+)-asocainol: 1.7 and 3.0; (+)-/(-)-tilidine: 1.1 and approximately equal to 2; (-)-(S)-/(+)-(R)- warfarin: 1.6 and 2.4; (+/-)-cis/(+/-)-trans-trans-tilidine: 1.7 and 1.8. When the calculation of radioligand-free fractions is also taken into account, it is apparent that only the tilidine isomers show no selectivity at propranolol-marked, and the disopyramide isomers at nicardipine-marked alpha 1-AGP-binding sites, in all other cases, a weak selectivity is detectable, which is, however, far below the values obtained for most neurotransmitter receptors. It is concluded that the single drug binding site of alpha 1-AGP is only slightly stereoselective and that the stereoselective binding of the drugs investigated is probably of no clinical consequence.