title: Predictive approaches to increase absorption of compounds during lead optimisation.
abstract: BACKGROUND
  Complex physicochemical and biological processes influence the oral absorption of a drug molecule. Consideration of these processes is an important activity during the optimisation of potential candidate molecules.
  
  
  METHODS
  The authors review the applications of physicochemical and structural requirements for intestinal absorption. Furthermore, they provide examples of how to aid the lead optimisation process through improvement of solubility and permeability.
  
  
  CONCLUSIONS
  The physicochemical requirements for absorption are solubility and permeability. Both are influenced by lipophilicity, but in the opposite way. The size of the molecule also affects both solubility and permeability. Several models can be used to estimate oral absorption from chemical structure or from measured physicochemical properties. Thus, logD-cMR model, the 'golden triangle' model, Abraham solvation equations and absorption potential can be used as tools in the lead optimisation process. Measured values of solubility and permeability greatly improve the estimation of in vivo oral absorption of compounds. However, it is important to appreciate that predictions of oral absorption may be confounded by the involvement of active transporters in the gut which may either increase (e.g., active uptake) or decrease (e.g., efflux) the absorption of drug molecules. To evaluate the first-pass metabolism, in vitro clearance measurements using liver microsomes can be used in physiologically based models for the estimation of bioavailability. The general tools discussed in this review are based on the physicochemical property assessment of compound libraries and they help design compounds that occupy desirable property space with increased likelihood of good oral absorption.
authors.affiliation: GlaxoSmithKline, Molecular Discovery Research, CSC-Analytical Chemistry , Gunnels Wood Road, Stevenage, Herts SG1 2NY , UK +01438 763 309 ; Klara.L.Valko@gsk.com.
authors.forename: Klara
authors.initials: K
authors.lastname: Valko
authors.forename: James
authors.initials: J
authors.lastname: Butler
authors.forename: Peter
authors.initials: P
authors.lastname: Eddershaw
mesh_terms: D000818:Animals; D001682:Biological Availability; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D007408:Intestinal Absorption; D008954:Models, Biological; D010539:Permeability; D004364:Pharmaceutical Preparations / Q000737:chemistry* / Q000378:metabolism*; D012995:Solubility; D013329:Structure-Activity Relationship
chemical_list: D004364:Pharmaceutical Preparations