Optimization of plasma protein binding (again…)


Following hot on the heels of the Pfizer paper we blogged recently, comes a very similar publication from scientists at Genentech/Depomed.  Titled ‘Do We Need to Optimize Plasma Protein and Tissue Binding in Drug Discovery?’, the authors highlight the apparent discrepancy between the practice of reducing protein binding in lead optimisation and the fact that many marketed drugs are highly protein bound.  They look to answer the question posed in the title using both empirical data and a more detailed theoretical analysis of the issue than that described in the earlier paper.  The conclusions they draw are, however, very similar:

  • Increasing drug free fraction alone leads to decreased total concentrations in vivo and has a negligible effect on the free drug concentration.
  • Increased drug free fraction will only increase free in vivo concentrations if hepatic clearance is also reduced.
  • The use of shift assays to weed out compounds with high levels of protein binding can lead to the premature termination of good molecules.  A better use of such assays is to determine the causes of the shifts observed (i.e. plasma protein binding or other factors).

The diagram below summarises these points nicely, illustrating the key differences between the in vitro and in vivo situation with respect to the effects of plasma protein binding on free concentration.

Increasing free fraction by 5-fold increases the unbound concentration by the same amount in vitro (total concentration is constant) but in vivo this increase is only observed when hepatic clearance is lowered (Scenario 1). When clearance is unchanged the total concentration is lowered (Scenario 2).

The authors go on to discuss the relationships between protein binding and intrinsic clearance, lipophilicity, and half-life before turning their attention to tissue binding.  The latter section looks at free brain concentrations in particular and makes the point that potency, the propensity for active efflux (e.g. P-gp), and hepatic clearance combine to have the biggest effect on efficacious clinical dose and that the free fraction in brain tissue is relatively unimportant.

This paper complements the earlier one from Pfizer nicely and reinforces all the same messages.  The empirical data included in the paper also nicely illustrates the points made by the authors.

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One Response to Optimization of plasma protein binding (again…)

  1. Ada says:

    That’s hot discussion over the years till present in 2015. Hope there will be more scientific evidence to prove which is better to human health.

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