title: 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.
authors.affiliation: Food and Drug Administration, Center for Drug Evaluation and Research, Office of Clinical Pharmacology and Biopharmaceutics, Rockville, Maryland 20852, USA. hinderlingp@cder.fda.gov
authors.forename: Peter H
authors.initials: PH
authors.lastname: Hinderling
authors.forename: Dieter
authors.initials: D
authors.lastname: Hartmann
mesh_terms: D000138:Acidosis / Q000378:metabolism / Q000503:physiopathology; D000471:Alkalosis / Q000378:metabolism / Q000503:physiopathology; D001798:Blood Proteins / Q000187:drug effects* / Q000378:metabolism*; D016206:Databases, Bibliographic; D016208:Databases, Factual; D006801:Humans; D006863:Hydrogen-Ion Concentration; D011485:Protein Binding / Q000187:drug effects; D016896:Treatment Outcome
chemical_list: D001798:Blood Proteins