The influence of lipophilicity on the pharmacokinetic behavior of drugs: Concepts and examples

Abstract

In this review, we first examine the contextual background of structure–pharmacokinetic relationships. Some concepts in drug disposition are briefly recalled, and inherent difficulties instructure–pharmacokinetic relationships are outlined. Lipophilicity is then investigated in the light of the intermolecular and intramolecular interactions it encodes. In the main body of the review, a number of pharmacokinetic processes are examined for their relations with lipophilicity. These processes are taken in a logical sequence of permeation, absorption (intestine, skin, cornea, brain), plasma protein binding, tissue distribution, volume of distribution and renal clearance. Relations between metabolism and lipophilicity are more complex, since biotransformation involves both low-energy (enzyme binding) and high-energy (catalysis) processes. Only the former may be related to lipophilicity. The conclusion argues against faulty statistics and over-interpretation.

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Testa, B., Crivori, P., Reist, M. et al. The influence of lipophilicity on the pharmacokinetic behavior of drugs: Concepts and examples. Perspectives in Drug Discovery and Design 19, 179–211 (2000). https://doi.org/10.1023/A:1008741731244

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  • adipose tissue storage
  • blood–brain barrier permeation
  • gastrointestinal absorption
  • lipophilicity
  • metabolism
  • permeation
  • plasma protein binding
  • renal clearance