Surface activity and concentration dependent intestinal permeability in the rat

Purpose. To investigate the relation between intestinal effective permeabil ity (P-eff) and surface activity of fluvastatin and verapamil. Methods. P-eff-values were determined for fluvastatin, antipyrine and D-glu cose Following colon perfusions in the rat in situ. The perfusion solutions differed regarding concentrations of fluvastatin (0-2500 mu M) and surface tension (58.9-43.7 mN/m). A cellulose derivative. ethyl (hydroxyethyl) cel lulose (EHEC), was added to lower the surface tension of one of the perfusi on solutions. The surface tension of perfusion solutions containing R/S-ver apamil (8-814 mu M) and R/S-verapamil + chlorpromazine (814 mu M + 10 mM) w ere related to the corresponding P-eff-values from the literature. Results. The P-eff of fluvastatin correlated inversely (r(2) = 0.985, p < 0 .05) with the surface tension of the perfusion solutions below the critical micelle concentration (CMC, 1 mM). Decreasing the surface tension with EHE C increased the P-eff of fluvastatin by 36% (p < 0.001), but not to the ext ent anticipated from the correlation between the P-eff and the surface tens ion. EHEC also increased the P-eff of antipyrine by 49% (p < 0.01) but not for D-glucose. The P-eff of R/S-verapamil correlated inversely with the sur face tension (r(2) = 0.980, p < 0.001). Conclusions. The ability of fluvastatin to decrease the surface tension at the membrane surface can partly explain the concentration dependent colonic P-eff of fluvastatin. This study shows that the surface activity of the dr ug molecule itself is an important physicochemical factor that should be ta ken into consideration when evaluating drug absorption studies performed in vitro or in situ.