The co-solvent Cremophor EL limits absorption of orally administered paclitaxel in cancer patients

Abstract

The purpose of this study was to investigate the effect of the co-solvents Cremophor EL and polysorbate 80 on the absorption of orally administered paclitaxel. 6 patients received in a randomized setting, one week apart oral paclitaxel 60 mg m−2 dissolved in polysorbate 80 or Cremophor EL. For 3 patients the amount of Cremophor EL was 5 ml m−2, for the other three 15 ml m−2. Prior to paclitaxel administration patients received 15 mg kg−1 oral cyclosporin A to enhance the oral absorption of the drug. Paclitaxel formulated in polysorbate 80 resulted in a significant increase in the maximal concentration (C max) and area under the concentration–time curve (AUC) of paclitaxel in comparison with the Cremophor EL formulations (P = 0.046 for both parameters). When formulated in Cremophor EL 15 ml m−2, paclitaxel C max and AUC values were 0.10 ± 0.06 μM and 1.29 ± 0.99 μM h−1, respectively, whereas these values were 0.31 ± 0.06 μM and 2.61 ± 1.54 μM h−1, respectively, when formulated in polysorbate 80. Faecal data revealed a decrease in excretion of unchanged paclitaxel for the polysorbate 80 formulation compared to the Cremophor EL formulations. The amount of paclitaxel excreted in faeces was significantly correlated with the amount of Cremophor EL excreted in faeces (P = 0.019). When formulated in Cremophor EL 15 ml m−2, paclitaxel excretion in faeces was 38.8 ± 13.0% of the administered dose, whereas this value was 18.3 ±15.5% for the polysorbate 80 formulation. The results show that the co-solvent Cremophor EL is an important factor limiting the absorption of orally administered paclitaxel from the intestinal lumen. They highlight the need for designing a better drug formulation in order to increase the usefulness of the oral route of paclitaxel © 2001 Cancer Research Campaign http://www.bjcancer.com

Oral bioavailability of a novel paclitaxel formulation (Genetaxyl) administered with cyclosporin A in cancer patients

“…Firstly, the median time to peak concentration of paclitaxel following oral Genetaxyl at 60 mg/m 2 was 1.5 hours, consistent with prior results showing that this parameter is lower when paclitaxel is administered in a formulation with lower concentrations of CrEL (1.5-2.9 versus 3.3-4.1 hours) [11,21]. This suggest that paclitaxel is absorbed more rapidly when the formulation contains no or less CrEL; it is possible that the rate of absorption of paclitaxel is affected by concentration-dependent entrapment of paclitaxel in CrEL micelles, thereby preventing paclitaxel from crossing the gastrointestinal membrane.…”

“…A prior study showed that a large fraction of both paclitaxel and CrEL was recovered unchanged in fecal samples after oral administration of Taxol [21], suggesting that the co-solvent CrEL could limit absorption of orally administrated paclitaxel by forming micelles entrapping the drug, without being itself absorbed [28]. Based on this finding, it was expected that the systemic exposure to paclitaxel after oral administration of Genetaxyl, containing 60% less CrEL as compared with Taxol, would be higher than those after administration of Taxol.…”

“…However, the apparent bioavailability of oral paclitaxel is still relatively low (about 30%), which is partly due to the presence of high concentrations (50%, v/v) of the formulation excipient Cremophor EL (CrEL), which limits drug absorption through the formation of micelles that entrap paclitaxel [21]. Furthermore, the high content of CrEL poses issues related to the calculation of bioavailability because its presence in the conventional paclitaxel formulation is associated with nonlinear drug disposition after i.v.…”

Genistein inhibits aggregation of exogenous amyloid-beta1–40 and alleviates astrogliosis in the hippocampus of rats

“…However, the mechanism by which CrEL improves the ability of neurons to resist Aβ is unknown. CrEL, used as a solvent for hydrophobic drugs, is associated with axonal damage in the peripheral nerves (Gelderblom et al, 2001), it has an antinociceptive effect (Tabarelli et al, 2003), and it limits the absorption of drugs in the gastrointestinal canal (Malingre et al, 2001). These observations show that the vehicle of drugs may have biological effects that influence the development of the pathology and, therefore, their effect should be considered before making any conclusion.…”

Supersaturated polymeric micelles for oral cyclosporine A delivery

“…The loading of risperidone into PEG-b-P(CL-co-TMC) micelles did not improve its permeability across Caco-2 monolayer [10]. Moreover, in some cases, PMs have been found to impede the absorption of hydrophobic drugs [11,12]. For example, Cremophor EL micelles have been shown to impair absorption of paclitaxel [12].…”