STEREOSELECTIVE BINDING OF ISRADIPINE TO HUMAN PLASMA-PROTEINS

Isradipine (PN 200-110) is a highly potent calcium entry blocker with an asymmetrically substituted dihydropyridine ring (methyl- and isopro pylester, respectively). The binding of the (+)-(S)-isradipine and (-) -(R)-isradipine to isolated human serum albumin (HSA, 30 mu mol/l) and alpha(1)-acid glycoprotein (AAG, 10 mu mol/l) has been studied in vit ro over a wide range of isradipine concentrations (0.06-20 mu mol/l) u sing high-performance liquid chromatography (HPLC). HPLC experiments r evealed that both isradipine enantiomers were bound to one class of hi gh-affinity binding sites on the AAG molecule (n((S)) = 0.83 +/- 0.05, K-a(S) = (1.33 +/- 0.25) x 10(6) l/mol, n((R)) = 0.85 +/- 0.07, K-a(R ) = (1.17 +/- 0.44) x 10(7) l/mol). The (R)-enantiomer also exhibited an interaction with the secondary low-affinity binding sites (n'K-a(R) ' = (2.66 +/- 0.65) x 10(4) l/mol). In contrast, the pharmacologically more potent (+)-(S)-enantiomer was more strongly bound to HSA than it s optical antipode (n((S)) = 1.07 +/- 0.07, K-a(S) = (1.76 +/- 0.26) x 10(5) l/mol, nK(a(R)) = (3.62 +/- 0.06) x 10(4) l/mol). In general, t he resulting binding characteristics of individual isradipine enantiom ers showed stereoselectivity, but this was opposite for the two most i mportant plasma binding proteins. The process of accumulation of israd ipine by human platelets in the therapeutically relevant range (10-80 ng/ml) at 37 degrees C was devoid of stereoselectivity. (C) 1995 Wiley -Liss, Inc.