Concentration and pH dependent aggregation of hydrophobic drug molecules and relevance to oral bioavailability

J Med Chem. 2005 Mar 24;48(6):1974-83. doi: 10.1021/jm049439i.


We have examined selected physicochemical properties of compounds from the diaryltriazine/diarylpyrimidine (DATA/DAPY) classes of non-nucleoside reverse transcriptase inhibitors (NNRTIs) and explored possible correlations with their bioavailability. In simple aqueous solutions designed to mimic the gastrointestinal (GI) environment of a fasting individual, all NNRTIs demonstrated formation of aggregates as detected by dynamic light scattering and electron microscopy. Under various conditions mimicking physiological transitions in the GI environment, aggregate size distributions were shown to depend on compound concentration and pH. NNRTIs with good absorption were capable of forming aggregates with hydrodynamic radii of </=100 nm at higher concentrations and over wide ranges of pH, while poorly absorbed inhibitors form aggregates with radii of >/=250 nm at concentrations above 0.01 mM, probably representing precipitate. We propose a model in which the uptake rate into systemic circulation depends on having hydrophobic drug aggregates of appropriate size available for absorption at different locations within the GI tract.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Absorption
  • Administration, Oral
  • Animals
  • Biological Availability*
  • Chemical Phenomena
  • Chemistry, Physical
  • Gastrointestinal Tract
  • Half-Life
  • Humans
  • Hydrogen-Ion Concentration
  • Hydrophobic and Hydrophilic Interactions
  • Light
  • Microscopy, Electron, Transmission
  • Models, Biological*
  • Pyrimidines / chemistry*
  • Rats
  • Reverse Transcriptase Inhibitors / chemistry*
  • Scattering, Radiation
  • Solutions
  • Triazines / chemistry*


  • Pyrimidines
  • Reverse Transcriptase Inhibitors
  • Solutions
  • Triazines