Enantioselective binding of propranolol, disopyramide, and verapamil to human alpha(1)-acid glycoprotein.
We investigated the binding of propranolol (PL), disopyramide (DP), and verapamil (VP) enantiomers by human alpha(1)-acid glycoprotein (AGP; also called orosomucoid) and the relationships between the extent of drug binding and lipophilicity, desialylation, and genetic variants of AGP. Desialylation had little effect on the affinity of AGP for the drugs tested. The percentage binding correlated significantly with the partition coefficients for the drugs tested. Each enantiomer was competitively displaced from AGP by another enantiomer of the same drug, suggesting that they bind to the same site. However, the enantiomers bound to AGP with stereospecific affinities; the (-)-isomers of DP and VP had higher Kd values (4.27 and 4.97 microM, respectively) than the (+)-isomers (1.51 and 2.48 microM, respectively). When enantiomers of the different drugs were used in competitive binding experiments, VP binding was only partially inhibited by DP. This result suggested that drug binding is specific to different variants of AGP (A, F1, S). DP was found to specifically bind to variant A, whereas PL and VP bind to both A and F1/S variants.
Hanada
K
K
Department of Biopharmaceutics, Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, Tokyo 204-8588, Japan.
Ohta
T
T
Hirai
M
M
Arai
M
M
Ogata
H
H
D004206:Disopyramide / Q000378:metabolism*; D006801:Humans; D009961:Orosomucoid / Q000378:metabolism*; D011433:Propranolol / Q000378:metabolism*; D011485:Protein Binding; D013237:Stereoisomerism; D014700:Verapamil / Q000378:metabolism*
D009961:Orosomucoid; D011433:Propranolol; D014700:Verapamil; D004206:Disopyramide