RT Journal Article
SR Electronic
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
FD American Society for Pharmacology and Experimental Therapeutics
SP 103
OP 106
VO 28
IS 2
A1 Andrew M. Davis
A1 Peter J. H. Webborn
A1 David W. Salt
YR 2000
UL http://dmd.aspetjournals.org/content/28/2/103.abstract
AB 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