Limited influence of P-glycoprotein on small-intestinal absorption of cilostazol, a high absorptive permeability drug.

Intestinal transport of the type III phosphodiesterase inhibitor cilostazol was characterized to evaluate the influence of secretory transporter. Intestinal absorption of cilostazol measured by the in situ closed loop method, showed regional differences, with high permeability in the upper part of the small intestine. Intestinal secretory transport of cilostazol at the ileum was tended to be decreased by the increase of tested concentration of cilostazol from 10 to 20 microM when evaluated by means of a Ussing-type chamber method with mounted rat intestinal tissues. Transcellular transport of cilostazol in the basolateral-to-apical direction in LLC-GA5-COL150 cells, which overexpress P-glycoprotein, was higher than that in parental LLC-PK1 cells. In addition, cilostazol reduced the basolateral-to-apical transport and increased the accumulation of [(3)H]daunomycin in LLC-GA5-COL150 cells. Accordingly, cilostazol was demonstrated to be transported by P-glycoprotein, while cilostazol is not likely to cause induction of the expression level of P-glycoprotein by the same manner with rifampin. Apical-to-basolateral transport of cilostazol in Caco-2 cells was increased in a low concentration range, followed by a decrease with further increase of the concentration, while the permeability coefficient of cilostazol was above 1 x 10(-6) cm/s at any concentration. Initial uptake of [(14)C]cilostazol by Caco-2 cells was temperature dependent and was reduced in the presence of unlabeled cilostazol, suggesting that apical uptake is also mediated by a transporter(s). In conclusion, intestinal absorption of cilostazol, which has a high absorptive permeability, may not be significantly hampered by efflux transporters, such as P-glycoprotein. Copyright 2003 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 92:2249-2259, 2003