Concentration and pH dependent aggregation of hydrophobic drug molecules and relevance to oral bioavailability.
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.
Frenkel
Yulia Volovik
YV
Center for Advanced Biotechnology and Medicine and Department of Chemistry and Chemical Biology, Rutgers University, 679 Hoes Lane, Piscataway, New Jersey 08854, USA.
Clark
Arthur D
AD
Das
Kalyan
K
Wang
Yuh-Hwa
YH
Lewi
Paul J
PJ
Janssen
Paul A J
PA
Arnold
Eddy
E
D000042:Absorption; D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D041981:Gastrointestinal Tract; D006207:Half-Life; D006801:Humans; D006863:Hydrogen-Ion Concentration; D057927:Hydrophobic and Hydrophilic Interactions; D008027:Light; D046529:Microscopy, Electron, Transmission; D008954:Models, Biological; D011743:Pyrimidines / Q000737:chemistry*; D051381:Rats; D018894:Reverse Transcriptase Inhibitors / Q000737:chemistry*; D012542:Scattering, Radiation; D012996:Solutions; D014227:Triazines / Q000737:chemistry*
D011743:Pyrimidines; D018894:Reverse Transcriptase Inhibitors; D012996:Solutions; D014227:Triazines