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Stereoselective binding of isradipine to human plasma proteins
Author(s) -
Oravcová Jana,
Sojková Dagmar,
Bencsíková Erika,
Bohov Pavol,
Trnovec Tomáš
Publication year - 1995
Publication title -
chirality
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.43
H-Index - 77
eISSN - 1520-636X
pISSN - 0899-0042
DOI - 10.1002/chir.530070311
Subject(s) - chemistry , isradipine , human plasma , stereoselectivity , stereochemistry , biochemistry , chromatography , receptor , catalysis , antagonist
Abstract Isradipine (PN 200–110) is a highly potent calcium entry blocker with an asymmetrically substituted dihydropyridine ring (methyl‐ and isopropylester, respectively). The binding of the (+)‐(S)‐isradipine and (−)‐(R)‐isradipine to isolated human serum albumin (HSA, 30 μmol/l) and α 1 ‐acid glycoprotein (AAG, 10 μmol/l) has been studied in vitro over a wide range of isradipine concentrations (0.06–20 μmol/l) using high‐performance liquid chromatography (HPLC). HPLC experiments revealed that both isradipine enantiomers were bound to one class of high‐affinity binding sites on the AAG molecule ( n (S) = 0.83 ± 0.05, K a ( S ) = (1.33 ± 0.25) × 10 6 1/mol, n (R) = 0.85 ± 0.07, K a(R) = (1.17 ± 0.44) × 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) × 10 4 l/mol). In contrast, the pharmacologically more potent (+)‐(S)‐enantiomer was more 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) = (3.62 ± 0.06) × 10 4 l/mol). In general, the resulting binding characteristics of individual isradipine enantiomers showed stereoselectivity, but this was opposite for the two most important plasma binding proteins. The process of accumulation of isradipine by human platelets in the therapeutically relevant range (10–80 ng/ml) at 37°C was devoid of stereoselectivity. © 1995 Wiley‐Liss, Inc.