Enhanced oral bioavailability of paclitaxel by coadministration of the P-glycoprotein inhibitor KR30031

Purpose. In an attempt to improve the oral bioavailability of paclitaxel, a novel P-glycoprotein inhibitor, KR30031, which is verapamil analog with fewer cardiovascular effects, was coadministered with paclitaxel, and to elucidate other possible causes of the low oral bioavailability of paclitaxel, an inhibitor of hepatic metabolism, ketoconazole, was also coadministered with paclitaxel. Methods. In vivo oral absorption was tested in rats, and an in vitro study was also performed with a Caco-2 cell monolayer to identify the extent of P-glycoprotein inhibition. Results. After coadministration of paclitaxel with ketoconazole, KR30031, or KR-30031 and ketoconazole, bioavailability was increased about 1.6-, 7.5-, or 8.9- fold as compared with control, respectively. These results show that P-glycoprotein plays a major role in the oral bioavailability of paclitaxel. The effect of ketoconazole on oral bioavailability of paclitaxel was limited relative to the P-glycoprotein inhibition effect of KR-30031. In vitro study of Caco-2 cell transport showed that paclitaxel permeation was significantly higher when the drug was given from the basolateral side as compared to the permeation from the apical side, indicating the involvement of an enzyme reaction in the active efflux mechanism. Apical-to-basolateral transport of paclitaxel was increased in the presence of KR-30031. The ability of KR-30031 to reduce this efflux transport is equal to that of verapamil, a well-known P-glycoprotein inhibitor. Conclusions. Our findings suggest that about 54% of a paclitaxel oral dose is extruded to the gut lumen by P-glycoprotein. Thus, the bioavailability of paclitaxel could be enhanced by coadministration of a P-glycoprotein inhibitor, KR-30031.