Induced correlations in the use of unbound/intrinsic pharmacokinetic parameters in quantitative structure-pharmacokinetic relationships with lipophilicity

The optimisation of pharmacokinetic properties remains one of the most chal lenging aspects of drug-design. Key parameters, clearance and volume of dis tribution are multifactorial which makes deriving structure-pharmacokinetic relationships difficult. The correction of clearance and volume of distrib ution for the unbound fraction in plasma, is one common approach that has b een taken to enable quantitative structure pharmacokinetic relationships to be derived. But this correction introduces a statistical ambiguity into th e analysis so severe, as to completely mislead the unaware. This paper exam ines this problem by analysing the correlation structure of two datasets.