The pH Dependency of the Binding of Drugs to Plasma Proteins in Man

Abstract

An analysis of pH-induced changes of drug binding may contribute to the understanding of the mechanisms involved and the clinical relevance. A literature search was performed, and acceptance criteria set up, to select reported data for quantitative evaluation. The relationship between percentage of unbound drug, fu, and pH was analyzed, and the relevance of physicochemical characteristics of the ligand drugs and the importance of hydrogen ion-induced changes in plasma proteins for the pH sensitivity of the binding were evaluated. With all basic and the majority of acidic drugs, fu depended linearly on pH. Basic drugs showed a consistent behavior with fu decreasing with increasing pH. Acidic compounds behaved differently: With some, fu increased, and with others fu decreased, with pH, and with a third group of acids fu was pH independent. Large differences in the pH sensitivity of the plasma protein binding among individual compounds were found. The fu in plasma for some bases and acids increased up to 136% and 95%, respectively, at pH values seen in severe acidemia or alkemia. These changes in fu could be clinically relevant with narrow-therapeutic-range drugs. Physicochemical properties and other characteristics of the ligands affect the pH sensitivity of the interaction with plasma proteins, but there was clear evidence indicating that pH-induced changes in the plasma proteins are also involved in the observed pH-dependent interaction with ligands. It is generally accepted that the unbound, free fraction in whole blood or plasma is an important determinant of the pharmacokinetics and pharmacodynamics of drugs. pH-dependent protein binding and consequent changes in the free fraction have been reported for many drugs. From a basic science point of view, the systematic study of pH-induced perturbations of the drug-protein interaction may provide insight into the mechanism and forces involved in the binding of drugs to plasma proteins. From a clinical viewpoint it may be of interest to know the extent of pH-induced changes in the unbound fraction of drugs under extreme acidemic or alkalemic conditions. Arterial blood pH values compatible with life reportedly range between 6.7 and 8.0. pH values as low as 6.3 have been measured in survivors of drowning accidents. To the best knowledge of the authors, a review and interpretation of pH-associated changes in the protein binding of drugs has not been attempted to date. The goals of this investigation were to (1) review published results of studies that determined the impact of pH changes on the protein binding of drugs in man, (2) select representative data using predetermined criteria, (3) determine relevant factors impacting the pH sensitivity of the drug-protein interaction, and (4) attempt to interpret the results and their clinical relevance.

Control and Measurement of Plasma pH in Equilibrium Dialysis: Influence on Drug Plasma Protein Binding

“…4, a-c, for which basic drugs in this pK a range show the most prominent shift in fup fold difference. For acids, the opposite would be expected; however, other groups have shown that some acids exhibit a decrease in fup with an increase in pH (Panjehshahin et al, 1992;Hinderling and Hartmann, 2005). We also observed this phenomenon for warfarin, which could potentially be due to a change in ionization of albumin, a charge-charge interaction with the lysine residue on albumin, or a change in conformation of albumin (Kasai-Morita et al, 1987).…”

“…It has been shown that an increase in plasma pH can have a significant influence on the extent of drug binding to plasma proteins (Paxton and Calder, 1983;Kremer et al, 1988;Hinderling and Hartmann, 2005;Wan and Rehngren, 2006;Kochansky et al, 2008). In attempts to address this issue, Wan and Rehngren (2006) determined that stronger buffers were required to minimize pH shifts, whereas others advocated the use of a 10% CO 2 atmosphere (Fura et al, 2003;Musteata et al, 2006;Kochansky et al, 2008) or initial purging of plasma with CO 2 followed by ultracentrifugation for determination of fup (Nilsson and Schmidt, 2001).…”

“…There is further discussion in the literature, supporting the use of either stronger buffer or incubation in a CO 2 atmosphere (Banker and Clark, 2008). Past studies have also examined the effect of a relatively wide postdialysis plasma pH range (of between pH 6 and 9) on fup (Hinderling and Hartmann, 2005;Wan and Rehngren, 2006). In a normal physiological state the in vivo arterial blood pH range is much narrower, within pH 7.…”

Postmortem redistribution of the heroin metabolites morphine and morphine-3-glucuronide in rabbits over 24 h

“…pH changes in the postmortem environment apart from changes in ionisation states may also alter the plasma protein binding of drugs (such as morphine) due to changes in protein structure and protein denaturation. Increasing the amount of morphine available to freely diffuse in the postmortem environment [39] .…”

Adult age and ex vivo protein binding of lorazepam, oxazepam and temazepam in healthy subjects

“…The fu of some drugs has been reported to rise with increasing temperature [20], but this is unlikely to be a significant issue in our study since previous reports used higher temperatures, and our fu values were slightly larger. Further, pH was not controlled, which is frequently the case with ultrafiltration [21]. This may be less relevant than for equilibrium dialysis because there is no exposure to an artificial buffer during ultrafiltration.…”