Correction of permeability with pore radius of tight junctions in Caco-2 monolayers improves the prediction of the dose fraction of hydrophilic drugs absorbed by humans.
OBJECTIVE
To improve predictions of fraction dose absorbed (Fa) for hydrophilic drugs, a correction of paracellular permeability using the pore radius of tight junctions (TJs) in Caco-2 monolayers was performed.


METHODS
The apparent permeability coefficient (P9app)) of drugs was measured using the Caco-2 assay and the parallel artificial membrane permeation assay (PAMPA), and values were corrected with the pore radius of TJs.


RESULTS
An equation for calculating the pore radius of TJs from the P(app) of lucifer yellow was obtained. The optimal pore radius of TJs in Caco-2 monolayers for predicting human Fa was calculated to be 7 A. The correlation between the actual and predicted Fa was improved by using the P(app) corrected with the pore radius of TJs. Permeability in the PAMPA, which was corrected using the pore radius and membrane potential, was well correlated with that in the Caco-2 assay. Most of the hydrophilic drugs tested in this study were absorbed mainly through the paracellular pathway.


CONCLUSIONS
The results suggest the necessity of optimizing paracellular permeation for the prediction of Fa, and also the importance of the paracellular pathway to the absorption of hydrophilic drugs. This method might contribute to the setting of appropriate dosages and the development of hydrophilic drugs.
Saitoh
Ryoichi
R
Fuji Gotemba Research Laboratories, Chugai Pharmaceutical Co., Ltd., Gotemba, Shizuoka 412-8513, Japan. saitorui@chugai-pharm.co.jp
Sugano
Kiyohiko
K
Takata
Noriyuki
N
Tachibana
Tatsuhiko
T
Higashida
Atsuko
A
Nabuchi
Yoshiaki
Y
Aso
Yoshinori
Y
D000042:Absorption; D000465:Algorithms; D018938:Caco-2 Cells; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D006801:Humans; D008567:Membranes, Artificial; D008954:Models, Biological; D010539:Permeability; D004364:Pharmaceutical Preparations / Q000737:chemistry / Q000378:metabolism*; D019108:Tight Junctions / Q000378:metabolism* / Q000648:ultrastructure*
D008567:Membranes, Artificial; D004364:Pharmaceutical Preparations