Entrapment by Cremophor EL decreases the absorption of paclitaxel from the gut

Background: Recent studies in mice and patients have shown that the low oral bioavailability of paclitaxel can be increased by coadministration of P-glycoprotein blockers. However, in patients an increase in the oral paclitaxel dose from 60 to 300 mg/m(2) does not result in proportionally higher plasma levels. We hypothesized that the surfactant Cremophor EL, present in the formulation of paclitaxel, may be responsible for this nonlinear absorption by entrapping paclitaxel within the intestinal lumen, probably by inclusion in micelles. Methods: Paclitaxel was administered to mdrlab P-glycoprotein knockout mice with either the conventional (controls) or a seven-fold higher amount of Cremophor EL (test group). Plasma, gastrointestinal tissues with their contents and faeces were collected and analysed by high-performance liquid chromatography to determine the levels of paclitaxel and Cremophor EL. The critical micellar concentrations of Cremophor EL in the contents of the small intestine were also established by an in vitro assay. Results: Paclitaxel recoveries in the faeces of the control and test groups were 7.6% and 35.8%, respectively. The peak plasma level and plasma AUC were reduced in the test group by about 75% and 40%, respectively. Only in mice from the test group did substantial quantities of paclitaxel together with Cremophor EL reach the caecum, thus passing through the small intestine. The concentration of Cremophor EL in the distal part of the small intestine and the caecum was 15 times higher in the test group and well above the critical micellar concentration of Cremophor EL. Conclusions: These results show that Cremophor EL prevents efficient uptake of paclitaxel from the gut, probably by entrapment within micelles. Other formulations should be developed for oral therapy with paclitaxel.