Journal of Computer-Aided Molecular Design

, Volume 15, Issue 3, pp 273–286 | Cite as

Lipophilicity in PK design: methyl, ethyl, futile

  • Han van de Waterbeemd
  • Dennis A. Smith
  • Barry C. Jones


Lipophilicity, often expressed as distribution coefficients (log D) in octanol/water, is an important physicochemical parameter influencing processes such as oral absorption, brain uptake and various pharmacokinetic (PK) properties. Increasing log D values increases oral absorption, plasma protein binding and volume of distribution. However, more lipophilic compounds also become more vulnerable to P450 metabolism, leading to higher clearance. Molecular size and hydrogen bonding capacity are two other properties often considered as important for membrane permeation and pharmacokinetics. Interrelationships among these physicochemical properties are discussed. Increasing size (molecular weight) often gives higher potency, but inevitably also leads to either higher lipophilicity, and hence poorer dissolution/solubility, or to more hydrogen bonding capacity, which limits oral absorption. Differences in optimal properties between gastrointestinal absorption and uptake into the brain are addressed. Special attention is given to the desired lipophilicity of CNS drugs. In examples using β-blockers, Ca channel antagonists and peptidic renin inhibitors we will demonstrate how potency and pharmacokinetic properties need to be balanced.

β-adrenoceptor antagonists calcium channel antagonists clearance hydrophobicity lipophilicity P450 metabolism P-glycoprotein plasma protein binding renin inhibitors volume of distribution 


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Copyright information

© Kluwer Academic Publishers 2001

Authors and Affiliations

  • Han van de Waterbeemd
    • 1
  • Dennis A. Smith
    • 1
  • Barry C. Jones
    • 1
  1. 1.Sandwich Laboratories, Department of Drug MetabolismPfizer Global Research and DevelopmentSandwich, KentUK

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