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

Yulia Volovik Frenkel, Arthur D. Clark, Kalyan Das, Yuh Hwa Wang, Paul J. Lewi, Paul A.J. Janssen, Eddy Arnold

Research output: Contribution to journalArticlepeer-review

118 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1974-1983
Number of pages10
JournalJournal of medicinal chemistry
Volume48
Issue number6
DOIs
StatePublished - Mar 24 2005

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

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