Comparative Binding of Two Closely Related Dihydropyridines (Isradipine and Darodipine) to Serum Proteins and Erythrocytes

Abstract

The binding of the two drugs isradipine and darodipine, chemically related to dihydropyridines and potent calcium channel blockers, was studied in vitro to isolated plasma proteins, erythrocytes and human serum. The two drugs were strongly bound to serum proteins (up to 97%), mainly to human serum albumin (HSA), α₁-glycoprotein (AAG) and lipoproteins (VLDL, LDL and HDL). Their bindings to AAG were saturable with high affinity constants (isradipine 498,000 M^–1, darodipine = 155,000 M^–1; n = 1). The binding of these drugs to HSA, VLDL and HDL was unsaturable, but it was saturable on LDL. In blood the drugs partitioned in erythrocytes, 16% for isradipine and 14.8% for darodipine.

Differences in the serum binding determinants of isradipine and darodipine‐consequences for serum protein binding in various diseases.

“…In contrast, HSA was responsible for 53.5% of the variability in the serum binding of darodipine, whereas AAG explained only 19% of the variability. The partial regression coefficients shown in Table 3 were very close to the binding parameters that were determined with isolated serum proteins in a previous study (Pinquier et al, 1988). In this report, the nK values for AAG and HSA were 0.498 ± 0.105 1 p.molF-and 0.034 ± 0.006 1 pLmol-1, respectively, for isradipine, and 0.…”

“…The non-zero values of the ordinate intercepts indicate that other proteins must influence the serum binding of the drugs. According to the results of our previous study (Pinquier et al, 1988), these are probably lipoproteins. Some of the variability in serum binding was not explained by AAG and HSA (38% for isradipine and 27.5% for darodipine).…”

“…In a (Fehske et al, 1980;Routledge, 1986a). The previous study, we have shown that these drugs variation in plasma binding of drugs is generally were bound to AAG with very different associamediated by variations in albumin concentration tion constants and to albumin with comparable for acidic drugs and by variations in AAG con-affinities (Pinquier et al, 1988). In keeping with centration for basic drugs (Routledge, 1986b).…”