Rational Use of Plasma Protein and Tissue Binding Data in Drug Design

The topic of protein binding has been a hot topic in recent years with a number of authors challenging the long held belief that simple in vitro measures of plasma protein binding or tissue binding can be used to accurately predict active drug concentrations. At recent article in J.Med Chem continues this debate. The authors perform both theoretical and empirical studies to show that low in vitro plasma protein binding is not necessarily predictive of a high unbound blood concentration in vivo, nor does low brain tissue binding accurately predict a high free CNS drug concentration.
The authors start by study a list of 169 recently approved drugs (2003-2013), all efficacious compounds of which 45% are > 95% plasma protein bound in vitro (figure 1)


The authors go on to describe experiments demonstrating the effects of protein binding in in vitro assays, on pharmacokinetic parameters and finally on free brain concentration. The summary of the extensive discussion is that protein binding measurements are of value in drug discovery programmes, however the picture is complex and data should never be used in isolation. Finally the authors make four recommendations for when and how to use plasma protein binding (PPB) data

  1. PPB should be determined to investigate if the potency shift is due to PPB.
  2. PPB should be determined in pharmacokinetic and pharmacodynamic (PK/PD) studies so that the relationship between in vivo free concentrations and in vitro free IC50 for the pharmacological target or toxicological targets can be assessed.
  3. PPB and brain tissue binding should be determined to calculate the unbound brain to unbound plasma concentration ratio in brain distribution assessment.
  4. In human clearance prediction studies, binding in the microsomes and hepatocytes should be considered.


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