Stereoselective binding of isradipine to human plasma proteins

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 mumol/l) and alpha 1-acid glycoprotein (AAG, 10 mumol/l) has been studied in vitro over a wide range of isradipine concentrations (0.06-20 mumol/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, Ka(S) = (1.33 +/- 0.25) x 10(6) l/mol, n(R) = 0.85 +/- 0.07, Ka(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'Ka'(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 its optical antipode (n(S) = 1.07 +/- 0.07, Ka(S) = (1.76 +/- 0.26) x 10(5) l/mol, nKa(R) = (3.62 +/- 0.06) x 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 degrees C was devoid of stereoselectivity.

Pharmacokinetics of Human Immunodeficiency Virus Protease Inhibitor, Nelfinavir, in Poloxamer 407-Induced Hyperlipidemic Model Rats

“…3,4) It has been reported that PI often induces hyperlipidemia (HL) as a side effect. [5][6][7] Furthermore, it has been reported that the lipoprotein binding function of high lipophilic drugs increases when lipoprotein increases in HL, [8][9][10] and that the clearance of cyclosporine A (CyA), a high lipophilic drug, decreased due to the increase of the lipoprotein level, as they are the major complexing constituents for CyA. 11,12) In our clinical study of CyA in renal transplant recipients, similar results were obtained 13) ; therefore, investigation of the relationship between the change of binding characteristics to serum protein (focusing on lipoproteins) and pharmacokinetics (PK) behavior in HL is important.…”

Stereoselective plasma protein binding of amlodipine

“…12 Opposite stereoselectivity for the enantiomers of HSA and AGP towards the dihydropyridine derivative isradipine has been reported, with the (R)-enantiomer binding more strongly to AGP but weaker to HSA compared with the (S)-enantiomer. 18 HSA and HP showed essentially comparable selectivity but a smaller effect was noted for HP. This may be explained by the fact that HP contains not only HSA but also other proteins such as globins or AGP.…”

“…Generally, HSA 2 and AGP 17 are well known to bind drugs stereoselectively and this has also been reported for other dihydropyridine calcium antagonists. 18,19 Interestingly, opposite chiral selectivity was observed for BSA and AGP on one hand and HSA on the other hand. Kubicek et al also reported the opposite stereoselectivity of the binding of the amlodipine enantiomers by HP and AGP with the (S)-amlodipine bound more strongly to HP, whereas (R)-amlodipine interacted stronger with AGP.…”

A Brief Review on Analytical Methods for Estimation of Isradipine in Pharmaceutical Formulation and Biological Matrices

“…The chromatographic separation was performed using an isocratic system with Chromspher C8 column (10 cm x 0.46 cm I.D., 5 μm particle size), detection of analytes wasmonitored at 240 nm using the photodiode array detector. The main objective of the proposed work is to measure the cytochrome P450 3A4 isoenzyme activity in h3A4 /OR cells [29].Oravcova et alperformed stereoselective binding of ISRA to human plasma proteins have been studied in vitro over an ISRA concentration (0.06-20 μmol/l) using HPLC [30]. On the same path.…”