Predicting oral absorption of drugs: a case study with a novel class of antimicrobial agents.
OBJECTIVE
The purpose of this work was to evaluate an oral absorption prediction model, maximum absorbable dose (MAD), which predicts a theoretical dose of drug that could be absorbed across rat intestine based on consideration of intestinal permeability, solute solubility, intestinal volume, and residence time.


METHODS
In the present study, Caco-2 cell permeability, as a surrogate for rat intestinal permeability, and aqueous solubility were measured for 27 oxazolidinones. The oxazolidinones are a novel class of potential antibacterial agents currently under investigation. These values were used to estimate MAD for each of the compounds. Finally, these predicted values were compared to previously measured bioavailability data in the rat in order to estimate oral absorption properties.


RESULTS
A reasonably good correlation between predicted dose absorbed and bioavailability was observed for most of the compounds. In a few cases involving relatively insoluble compounds, absorption was underestimated. For these compounds while aqueous solubility was low. solubility in 5% polysorbate 80 was significantly higher, a solvent possibly more representative of the small intestinal lumen.


CONCLUSIONS
These results suggest that MAD may be useful for prioritizing early discovery candidates with respect to oral absorption potential. In the case of compounds with poor aqueous solubility, additional factors may have to be considered such as solubility in the intestinal lumen.
Hilgers
Allen R
AR
Drug Absorption and Transport, Global Pharmaceutical Sciences, Pharmacia, Kalamazoo, 49007, USA.
Smith
Donald P
DP
Biermacher
John J
JJ
Day
Jeffrey S
JS
Jensen
Jana L
JL
Sims
Sandra M
SM
Adams
Wade J
WJ
Friis
Janice M
JM
Palandra
Joe
J
Hosley
John D
JD
Shobe
Eric M
EM
Burton
Philip S
PS
D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D001692:Biological Transport; D018938:Caco-2 Cells; D006801:Humans; D007275:Injections, Intravenous; D007408:Intestinal Absorption; D008954:Models, Biological; D023303:Oxazolidinones / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D051381:Rats; D012995:Solubility; D012997:Solvents
D023303:Oxazolidinones; D012997:Solvents