Increased oral bioavailability of paclitaxel by GF120918 in mice through selective modulation of P-glycoprotein

Previous studies in mice with disrupted mdrla P-glycoprotein genes have sho wn that the oral bioavailability of paclitaxel is very low because of the p resence of this drug-transporting protein in the intestinal wall. Additiona l studies with cyclosporin A have shown that this P-glycoprotein-inhibiting agent is able to increase the bioavailability of paclitaxel in mouse model s and in patients. However, the potential immune-suppressive side effects o f cyclosporin A renders this compound less suitable for chronic use in canc er patients. In this paper we present the results obtained with GF120918, a n experimental P-glycoprotein inhibitor, on the oral bioavailability of pac litaxel in both wild-type and mdr1ab knockout mice. GF120918 (25 mg/kg) was administered p.o. by gavage 15 min or 2 h before oral or i.v. dosing of pa clitaxel, respectively. Paclitaxel plasma levels were quantified by high-pe rformance liquid chromatography. GF120918 increased the plasma values for a reas under the concentration-time curve of oral paclitaxel in wild-type mic e by 6.6-fold from 408 to 2701 ng(.)ml(-1.)h. Calculated relative to their respective values for area under the concentration-time curve after i.v. ad ministration, GF120918 increased the oral bioavailability of paclitaxel in wild-type mice from 8.5 to 40.2%. The plasma pharmacokinetics of paclitaxel in mdr1ab knockout mice was not altered by GF120918, whereas the pharmacok inetics of paclitaxel in wild-type mice receiving GF120918 became comparabl e with mdr1ab knockout mice, This result indicates that GF120918 at this do se-level selectively and completely blocks P-glycoprotein in the intestines and does not notably Interfere in the elimination of paclitaxel by metabol ism or other transporters. On the basis of this result, GF120918 has been s elected for additional study in humans.