Opposite stereoselectivity of two plasma binding proteins for isradipine (PN 200-110)

Abstract

The binding of isradipine (PN 200-110) and its enantiomers to isolated human serum albumin (HSA) and α 1-acid glycoprotein (AAG) has been studied over a wide range of isradipine concentrations (0.06–20 μmol/l) using a high-performance liquid chromatography (HPLC). The binding parameters of isradipine racemate were similar to those previously reported (AAG: n (RS) = 0.96 ± 0.04, K a = (2.72 ± 0.49) × 10 6 l/mol; HSA: n (RS) = 1.05 ± 0.12, K a = (1.56 ± 0.30) × 10 5 l/mol). The experiments revealed that both isradipine enantiomers were bound to one class of high affinity binding sites on AAG molecule and that the r-isradipine was bound preferentially ( n (S) = 0.83 ± 0.05, K a(S) = (1.33 ± 0.25) × 10 6 l/mol, n (R) = 0.85 ± 0.07, K a(R) = (1.17 ± 0.45) × 10 7 l/mol). On the other hand, the pharmacologically more potent strongly bound to HSA than its optical antipode ( n(S) = 1.07 ± 0.07, K a(S) = (1.76 ± 0.26) × 10 5 l/mol, nK a( R) (nonsp binding) = (3.62 ± 0.06) × 10 4 l/ mol). The resulting binding characteristics of individual isradipine enantiomers showed stereoselectivity which is, however, opposite for the two most important plasma binding proteins.