The effect of Ca⁺⁺ on the binding of drugs to human serum albumin: Pharmacokinetic implications

Abstract

A Recenthave shown dramatic effects of C a + + on the binding of drugs to human serum albumin (HSA). For example, dialysis studies showed that the binding of warfarin was increased over the pH range 5-9 following the addition of C a + + . This was apparently due to the effect of the ion on the N-B (neutral-basic) equilibrium of the HSA, the equilibrium occurring over this same pH range. On the other hand CI-at physiological concentrations was found to reduce the binding of warfarin to HSA by a competitive binding mechanism. Subsequently M g + + was found to reduce the binding of warfarin to HSA when the protein was in the B form, but there was little effect at the physiological P H .~ On the other hand Ca+ + was found to reduce the binding of diazepam3 and benoxaprofen4 to HSA, over the pH range of the N-B conformational change. These drugs do not share a primary binding site with warfarin.'. ' This phenomenon may be due to competition between Ca' + and the drugs for the imidazole residues at the binding sites.4 The interesting possibility arises of Ca+ + being used as a marker to determine which of the two major and independent binding sites (the warfarin or the diazepam site') on HSA, a given drug has as its primary binding site. The work reported in Table 1 was primarily designed to test this possibility.Dialysis was conducted as previously described2a4 using 0.1 M sodium chloride with the pH adjusted with sodium hydroxide or hydrochloric acid, with and without 2.5 x M calcium chloride at 25". N o clear cut pattern arises as far as the assignment of binding sites from the effect of the C a + + on the extent of binding. This is assuming that the assignment of binding sites in the literature is correct.'. ' The data in the table, especially for salicyclic acid, phenytoin, dicumarol, ibuprofen, diazepam, and benoxaprofen, stress the dramatic effect C a + + can have on the extent of binding of drugs to HSA and, although 0

Protein binding of lidocaine in canine serum and plasma: Effects of an acidic pH and the technique of study

“…Ultrafiltration appears to be more appropriate than dialysis techniques because it can be carried out rapidly without the addition of potentially competitive buffer components' or dilution of plasma or serum electrolytes. 6 The purpose of this investigation was to determine the plasma and serum protein binding of lidocaine in the dog with doses equal to those used in man. Since the central nervous system toxicity effect of local anaesthetics increases with respiratory acidosis: the influence of a moderately acidic pH on the protein binding of lidocaine was also examined.…”

On the modulating effects of temperature, albumin, pH and calcium on the free fractions of phenobarbitone and phenytoin

“…Protein binding may also be affected by the presence of competing (or otherwise interfering) substances, for example as in uraemia (Reidenberg et a1 1971;Shoeman & Azarnoff 1972), or as a result of polypharmacy (Fraser 1980). Also, changes in the concentration of electrolytes such as H + , Ca2f and c1can influence albumin drug binding (Vallner et a1 1979;Perrin & Juni 1982;Shaw et a1 1982).…”