Small molecule kinase inhibitors approved by the FDA from 2000 to 2011: a systematic review of preclinical ADME data

Expert Opin Drug Metab Toxicol. 2013 Dec;9(12):1597-612. doi: 10.1517/17425255.2013.834046. Epub 2013 Aug 31.


Introduction: Fourteen drugs targeting protein kinases have been approved by the United States Food and Drug Administration (FDA) between the years 2000 and 2011. While the mechanisms of action and clinical data have been reported, the preclinical absorption, distribution, metabolism and elimination (ADME) data on these compounds are not readily available.

Areas covered: This review summarizes the structural, physicochemical and preclinical ADME properties of the 14 kinase inhibitors. For this purpose, the authors identified common preclinical ADME features of the majority of these inhibitors.

Expert opinion: The authors believe engendering a combination of the following attributes will greatly improve one's chance of discovering kinase inhibitors with a successful development path: i) Lipinski Rule of Five and Veber's rules, ii) most basic pKa values ≤ 9, iii) low to moderate clearance values for each species and iv) moderate to high Caco-2 permeability. Furthermore, they recommend primarily focusing on in vitro hepatic stability and rodent in vivo disposition properties at early screening stage and using Caco-2 permeability/efflux ratio to salvage compounds with rapid rodent plasma clearance. In vitro drug-drug interaction data should be evaluated in the context of the dosing route, dosing regimen, elimination pathways, enzyme phenotyping profile, efficacious exposure and the target disease.

Publication types

  • Review
  • Systematic Review

MeSH terms

  • Biological Availability
  • Caco-2 Cells
  • Chemical Phenomena
  • Cytochrome P-450 CYP3A / metabolism
  • Drug Evaluation, Preclinical
  • Drug Interactions
  • Humans
  • Permeability
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / pharmacokinetics*
  • Solubility
  • United States
  • United States Food and Drug Administration


  • Protein Kinase Inhibitors
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human