It is a commonly accepted assumption that only free drug molecules are available to interact with drug targets. Therefore, one of the objectives in drug design is to optimize the compound structure to increase in vivo free drug concentration and to enhance pharmacological activities. In this presentation, theoretical analyses and experimental observations will be discussed to highlight the differences between free fraction and free concentration and to illustrate that low plasma protein binding (high free fraction) can result in high free concentration in vitro but does not necessarily lead to high in vivo free concentration following oral drug administration. Similarly, low brain tissue binding can result in high free concentration in vitro but does not necessarily lead to high in vivo free brain tissue concentration. Instead, low intrinsic clearance leads to high in vivo free plasma concentration and low efflux transport activity at the blood-brain barrier leads to high free brain concentration. Plasma protein and brain tissue binding are very important parameters in understanding pharmacokinetics, pharmacodynamics, and toxicities of drugs but these parameters should not be targeted for optimization in drug design. Instead we should focus on reducing clearance and efflux at the blood-brain barrier to increase in vivo plasma and tissue free concentration.

Considerations of plasma protein and tissue binding in drug design

251st National Meeting (2016)

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