TY - JOUR T1 - Robust Assessment of Statistical Significance in the Use of Unbound/Intrinsic Pharmacokinetic Parameters in Quantitative Structure–Pharmacokinetic Relationships with Lipophilicity JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 103 LP - 106 VL - 28 IS - 2 AU - Andrew M. Davis AU - Peter J. H. Webborn AU - David W. Salt Y1 - 2000/02/01 UR - http://dmd.aspetjournals.org/content/28/2/103.abstract N2 - The optimization of pharmacokinetic properties remains one of the most challenging aspects of drug design. Key parameters, clearance and volume of distribution, are multifactorial, which makes deriving structure-pharmacokinetic relationships difficult. The correction of clearance and volume of distribution for the unbound fraction in plasma is one approach taken that has enabled quantitative structure-pharmacokinetic relationships to be derived. Three published data-sets where unbound parameters have been correlated with lipophilicity have been reanalyzed. The reanalysis has shown that high correlation coefficients can be achieved without any true correlation in the data and can lead to misinterpretation of the ways in which lipophilicity influences pharmacokinetics. Randomization procedures are proposed as a more robust method of assessing significance. The American Society for Pharmacology and Experimental Therapeutics ER -