Effect of nanonization on absorption of 301029:: Ex vivo and in vivo pharmacokinetic correlations determined by liquid chromatography/mass spectrometry

Purpose. To compare Caco-2 monolayer permeability and in vivo bioavailability of microparticle with nanoparticle 301029, a thiadiazole derivative, and to determine whether nanonization could improve oral bioavailability of the poorly soluble compound. Methods. The mean particle size of 301029 was reduced from 7 mum to 280 nm by pearl milling. In the ex vivo assay, both microparticle and nanoparticle 301029 at the same concentration were separately added to apical side and were collected from basolateral side of Caco-2 monolayer. In the bioavailability study, the two particle sizes of 301029 were orally administered to rats, respectively, and blood samples were collected. Nanoparticle 301029 in culture medium and rat serum was detected by a liquid chomatography-mass spectrometer (LC/MS) coupled with atmospheric pressure chemical ionization (APCI). Results. Permeability rate and permeated amounts of nanoparticle 301029 across the Caco-2 monolayer were about four times higher than those of microparticle 301029. In a pharmacokinetic study, nanoparticle 301029 showed T-max about 1 h, whereas the microparticle 301029 showed T-max at 4 h. The C-max and AUC of nanoparticle 301029 were 3- to 4-fold greater than those of microparticle 301029, resulting in a significant increase in oral bioavailability of 301029 as compared with microparticle 301029. The ex vivo permeability and in vivo pharmacokinetic data indicate that nanoparticle formulation improves both absorption rate and absorption extent of the poorly soluble drug. Conclusions. Nanoparticle formulation enhances both Caco-2 monolayer permeability and rat oral bioavailability of the poorly soluble 301029. The result also demonstrates a close correlation between ex vivo Caco-2 permeability model and in vivo gastrointestinal absorption.