Misconceptions in Unbound Volume of Distribution and Their Implications for Pharmacokinetic Scaling and Drug Design

Unbound volume of distribution is sometimes treated as an intrinsic, species-invariant property. Mechanistic analysis shows that it can be influenced by plasma protein binding through tissueplasma binding relationships, and that assuming constant tissue binding across species is not generally valid. Case evidence and modeling indicate that modulating plasma protein binding can meaningfully affect half-life and hepatic extraction, thereby improving oral bioavailability and in vivo efficacy. These insights argue for revisiting common cross-species scaling practices and for considering plasma protein binding as an explicit design parameter.