Vol. 297, Issue 2, 547-555, May 2001

Contribution of P-glycoprotein to the Enhancing Effects of Dimethyl--cyclodextrin on Oral Bioavailability of Tacrolimus

Hidetoshi Arima, Kiyokazu Yunomae, Fumitoshi Hirayama and Kaneto Uekama

Faculty of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan

We recently reported that of all hydrophilic cyclodextrin (CyD) derivatives examined, 2,6-di-O-methyl--cyclodextrin (DM--CyD) most significantly increased the aqueous solubility and the dissolution rate, resulting in the improvement of oral bioavailability of the immunosuppressive drug tacrolimus in rats. In the present study, we showed that DM--CyD increased the dissolution rate and oral bioavailability of tacrolimus in rats with increases in the molar ratio of the complexes (DM--CyD:tacrolimus). However, nonlinear pharmacokinetic behavior of tacrolimus after oral administration in rats was observed. Thus, an additional mechanism of the solubilizing effect of DM--CyD on oral bioavailability of tacrolimus was postulated. To gain insight into this additional mechanism of action of DM--CyD, its effects on the efflux of tacrolimus and rhodamine 123, a P-glycoprotein (P-gp) substrate, were examined using both Caco-2 and vinblastine-resistant Caco-2 (Caco-2R) cell monolayers. Pretreatment of the apical membranes of the monolayers with DM--CyD decreased the efflux of tacrolimus and rhodamine 123 without an associated cytotoxicity. DM--CyD decreased the P-gp level in the apical membranes of both Caco-2 and Caco-2R cell monolayers, probably by allowing release of P-gp from the apical membrane into the transport buffer. DM--CyD, however, did not decrease the MDR1 gene expression in Caco-2 or Caco-2R cells. These results suggested that the enhancing effect of DM--CyD on the oral bioavailability of tacrolimus is due not only to its solubilizing effect but also, at least in part, to its inhibitory effect on the P-gp-mediated efflux of tacrolimus from intestinal epithelial cells.