title: Application of simple mathematical expressions to relate the half-lives of xenobiotics in rats to values in humans.
abstract: BACKGROUND
  Previous publications from GlaxoSmithKline and University of Toledo laboratories convey our independent attempts to predict the half-lives of xenobiotics in humans using data obtained from rats. The present investigation was conducted to compare the performance of our published models against a common dataset obtained by merging the two sets of rat versus human half-life (hHL) data previously used by each laboratory.
  
  
  METHODS
  After combining data, mathematical analyses were undertaken by deploying both of our previous models, namely the use of an empirical algorithm based on a best-fit model and the use of rat-to-human liver blood flow ratios as a half-life correction factor. Both qualitative and quantitative analyses were performed, as well as evaluation of the impact of molecular properties on predictability.
  
  
  RESULTS
  The merged dataset was remarkably diverse with respect to physiochemical and pharmacokinetic (PK) properties. Application of both models revealed similar predictability, depending upon the measure of stipulated accuracy. Certain molecular features, particularly rotatable bond count and pK(a), appeared to influence the accuracy of prediction.
  
  
  CONCLUSIONS
  This collaborative effort has resulted in an improved understanding and appreciation of the value of rats to serve as a surrogate for the prediction of xenobiotic half-lives in humans when clinical pharmacokinetic studies are not possible or practicable.
authors.affiliation: Preclinical Drug Discovery, Cardiovascular and Urogenital CEDD, GlaxoSmithKline, UW 2725, 709 Swedeland Road, King of Prussia, PA 19406, USA. Keith_W_Ward@gsk.com
authors.forename: Keith W
authors.initials: KW
authors.lastname: Ward
authors.forename: Paul
authors.initials: P
authors.lastname: Erhardt
authors.forename: Kenneth
authors.initials: K
authors.lastname: Bachmann
mesh_terms: D000465:Algorithms; D000818:Animals; D003625:Data Collection; D006207:Half-Life; D006801:Humans; D008099:Liver / Q000098:blood supply; D008433:Mathematics; D011237:Predictive Value of Tests; D051381:Rats; D013223:Statistics as Topic; D018675:Toxicity Tests; D015262:Xenobiotics / Q000737:chemistry / Q000493:pharmacokinetics*
chemical_list: D015262:Xenobiotics