A time hierarchy-based model for kinetics of drug disposition and its use in quantitative structure-activity relationships

J Pharm Sci. 1992 Sep;81(9):849-57. doi: 10.1002/jps.2600810902.

Abstract

By using the time hierarchy of the processes determining the fate of drugs in biosystems (absorption, transport, distribution, protein binding, and elimination), a one-compartment open model is formulated at a subcellular level for the disposition phase of pharmacokinetics. The resulting disposition function describes the kinetics of the intracellular disposition of drugs as determined by their hydrophobicity, acidity or basicity, affinity to proteins, and rate parameters of elimination. Structure-activity relationships, based on the function with incorporated extrathermodynamic relations, fit the literature data well (fixed-time bioactivity-hydrophobicity profiles, kinetics of microbial degradation of organic compounds, and kinetics of analgesic effects of fentanyl derivatives in rats). Application of the approach, creating a basis for the construction of model-based quantitative structure-time-activity relationship, to biosystems of varying complexity is discussed.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biodegradation, Environmental
  • Humans
  • Models, Biological*
  • Pharmacokinetics*
  • Solubility
  • Structure-Activity Relationship