REVIEW Significance of Protein Binding in Pharmacokinetics and Pharmacodynamics STEPHAN SCHMIDT, 1,2 DANIEL GONZALEZ, 1 HARTMUT DERENDORF 1 1 Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, Florida 2 Leiden-Amsterdam Center for Drug Research, Division of Pharmacology, University of Leiden, Leiden, the Netherlands Received 6 May 2009; revised 21 July 2009; accepted 22 July 2009 Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jps.21916 ABSTRACT: The significance of plasma protein binding on drug efficacy and, subse- quently, the clinical relevance of changes in protein binding has been controversially discussed for decades. The uncertainty concerning the impact of plasma protein binding on a drug’s pharmacological activity is, in part, related to the approach used when investigating and interpreting protein binding effects in vitro and in vivo. Frequently, a generalized one-size-fits-all approach, such as ‘‘protein binding does matter/does not matter,’’ may not be applicable. An appropriate analysis requires careful consideration of both pharmacokinetic and pharmacodynamic processes, as they both contribute to the safety and efficacy of drugs. Therefore, the aim of this article is to provide a concise review of the theoretical concepts of protein binding, and to discuss relevant examples where applicable. ß 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci Keywords: protein binding; pharmacokinetics; pharmacodynamics; clearance; drug effects INTRODUCTION The effect of protein binding on the pharmacolo- gical activity of drugs seems to be a source of sheer never-ending debate. 1–5 It is well known that the pharmacological effect of a drug is dependent on both its pharmacokinetic and pharmacodynamic properties, and thus the effects of protein binding on both of these disciplines requires careful consideration. Several authors have highlighted scenarios where an alteration in a protein binding may result in clinically significant changes in the pharmacokinetics (PK) of a drug. 2,6–11 In compar- ison, fewer articles are available, which outline the effects of protein binding on drug action. It is often much more difficult to make generally applicable statements about the effects of protein binding on the pharmacodynamics (PD) of a drug, since a plethora of factors need to be considered. These factors include the drug’s mechanism of action, the drug’s affinity for the drug target (and protein), the number of drug binding sites on the target (and protein), location of the effect site, as well as the protein concentration directly at the effect site. 3 As a consequence, a case-by-case evaluation is needed to appropriately address the protein binding effects on the PK and PD of a drug. Moreover, disagreements on its significance are, in part, a result of how protein binding effects are investigated and interpreted. For Correspondence to: Hartmut Derendorf (Telephone: þ1-352-273-7856; Fax: þ1-352-392-3249; E-mail: hartmut@ufl.edu) Journal of Pharmaceutical Sciences ß 2009 Wiley-Liss, Inc. and the American Pharmacists Association JOURNAL OF PHARMACEUTICAL SCIENCES 1