Drug liposome partitioning as a tool for the prediction of human passive intestinal absorption.
OBJECTIVE
Appropriate physicochemical parameters are desired for the prediction of passive intestinal drug absorption during lead compound selection and drug development.


METHODS
Liposome distribution coefficients measured titrimetrically and solubility data at pH 6.8 were used to characterize 21 structurally diverse ionizable drugs covering a range from <5% to almost complete absorption.


RESULTS
A sigmoidal relationship was found between the percentage of human passive intestinal absorption and a new absorption potential parameter calculated from liposome distribution data and the solubility-dose ratio. In contrast, the human absorption data did not correlate with an octanol-based absorption potential or partitioning data alone. Poor correlations were found between liposome and octanol partitioning of ionic species or nonionic bases indicating the profound differences of the partitioning systems.


CONCLUSIONS
Liposome distribution coefficients of ionizable drugs derived by a pH-metric titration were successfully used to calculate a parameter that correlates with the percentage of passive intestinal absorption in humans. Profound differences between liposome and octanol partitioning were found for a highly diverse set of species. This titration technique may serve to generate liposome partitioning data for the selection and optimization of lead compounds and in drug development.
Balon
K
K
Lilly Forschung GmbH, Pharmaceutical Product Development, Hamburg, Germany.
Riebesehl
B U
BU
Müller
B W
BW
D006801:Humans; D007408:Intestinal Absorption; D008081:Liposomes / Q000737:chemistry* / Q000493:pharmacokinetics; D000442:Octanols / Q000737:chemistry / Q000493:pharmacokinetics; D012995:Solubility
D008081:Liposomes; D000442:Octanols