Permeability is an underlying parameter to control drug absorption. For highly water-soluble drugs, the high correlation between their permeability and fraction absorbed in humans is reported. In the present study, to predict the absorbability of poorly water-soluble drugs in humans, a new experimental method of the permeation study was proposed and subjected to examination.
Firstly, using the
in vitro chamber method modified to contain 5% (final concentration) dimethyl sulufoxide (DMSO) in both compartments of the chamber (DMSO-MS), the effect of DMSO on membrane integrity was evaluated. Secondly, the correlation between the apparent permeability coefficients (P
app) obtained through DMSO-M or DMSO-MS and fractions absorbed in humans were investigated using 7 poorly water-soluble drugs.
Membrane integrity of the rat intestinal tissues was maintained after using DMSO-MS, as with that after using the conventional
in vitro chamber method. P
app of two paracellular markers obtained through DMSO-MS was not different from that obtained through the conventional chamber method. In the permeation study of the P-glycoprotein substrate, P
app from both mucosal to serosal and serosal to mucosal sides obtained through DMSO-MS was not significantly different from that obtained through the conventional chamber method. The correlation between P
app obtained through DMSO-MS and F
a which was expressed by the equation of F
a=1-exp (-P
app×1.38×10
5) (r
2=0.980), was more favorable than the correlation between
Papp obtained through DMSO-M and F
a which was expressed by the equation of F
a=1-exp (-P
app×2.12×10
5) (r
2=0.875).
These results showed that DMSO-MS was a useful method for predicting the absorbability of poorly water-soluble drugs.
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