Influence of lipophilicity and lysosomal accumulation on tissue distribution kinetics of basic drugs: a physiologically based pharmacokinetic model

Methods Find Exp Clin Pharmacol. 2002 Mar;24(2):81-93. doi: 10.1358/mf.2002.24.2.677131.


This paper examines the role of lipophilicity in the tissue distribution kinetics of basic drugs. Basic drugs have a large distribution volume and are distributed widely in various tissues in the following order: lung, fat, heart, kidney, brain, gut, muscle and bone. The fat volume in the whole body influences the disposition kinetics. There is a good correlation in various tissues between the tissue-plasma concentration ratio and the octanol-water partition coefficient among various drugs. We constructed a physiologically-based pharmacokinetic model on the basis of drug lipophilicity and found that drug distribution decreased when NH4Cl was administered concomitantly. In regards to subcellular distribution, the relative specific contents of chlorpromazine, imipramine and biperiden with respect to the protein in lysosomes were 7.3, 9.6 and 4.2, respectively, while those in other subcellular organella, including mitochondria, were only 0.4-1.7, indicating preferential accumulation of these drugs in lysosomes. The uptake of basic drugs into lysosomes depended on both intralysosomal pH and drug lipophilicity. As the lipophilicity of the basic drugs increased, they accumulated more than would have been predicted from the pH-partition theory and raised the intralysosomal pH more potently, probably owing to their binding with lysosomal membranes, with or without intralysosomal aggregation. We conclude that the distribution kinetics of basic drugs is driven by drug lipophilicity and uptake into lysosomes, and these phenomena provide a possible basis for drug interaction in clinical treatments.

MeSH terms

  • Animals
  • Biperiden / pharmacokinetics
  • Dogs
  • Lipids
  • Lysosomes / metabolism
  • Models, Biological*
  • Pharmaceutical Preparations / chemistry*
  • Pharmacokinetics*
  • Rabbits
  • Rats
  • Solubility
  • Tissue Distribution


  • Lipids
  • Pharmaceutical Preparations
  • Biperiden