[show abstract][hide abstract] ABSTRACT: The anticancer drug paclitaxel is formulated for i.v. administration in a mixture of Cremophor EL and ethanol. Its oral bioavailability is very low due to the action of P-glycoprotein in the gut wall and CYP450 in gut wall and liver. However, proof-of-concept studies using the i.v. formulation diluted in drinking water have demonstrated the feasibility of the oral route as an alternative when given in combination with inhibitors of P-glycoprotein and CYP450. Because of the unacceptable pharmaceutical properties of the drinking solution, a better formulation for oral application is needed. We have evaluated the suitability of various self-micro emulsifying oily formulations (SMEOF's) of paclitaxel for oral application using wild-type and P-glycoprotein knockout mice and cyclosporin A (CsA) as P-glycoprotein and CYP450 inhibitor. The oral bioavailability of paclitaxel in all SMEOF's without concomitant CsA was low in wild-type mice, showing that this vehicle does not enhance intestinal uptake by itself. Paclitaxel (10 mg/kg) in SMEOF#3 given with CsA resulted in plasma levels that were comparable to the Cremophor EL-ethanol containing drinking solution plus CsA. Whereas the AUC increased linearly with the oral paclitaxel dose in P-glycoprotein knockout mice, it increased less than proportional in wild-type mice given with CsA. In both strains more unchanged paclitaxel was recovered in the feces at higher doses. This observation most likely reflects more profound precipitation of paclitaxel within the gastro-intestinal tract at higher doses. The resulting absolute reduction in absorption of paclitaxel from the gut was possibly concealed by partial saturation of first-pass metabolism when P-glycoprotein was absent. In conclusion, SMEOF's maybe a useful vehicle for oral delivery of paclitaxel in combination with CsA, although the physical stability within the gastro-intestinal tract remains a critical issue, especially when applied at higher dose levels.
Investigational New Drugs 04/2010; · 3.50 Impact Factor
[show abstract][hide abstract] ABSTRACT: To explore the parmacokinetics, safety and tolerability of paclitaxel after oral administration of SMEOF#3, a novel Self-Microemulsifying Oily Formulation, in combination with cyclosporin A (CsA) in patients with advanced cancer. Seven patients were enrolled and randomly assigned to receive oral paclitaxel (SMEOF#3) 160 mg+CsA 700 mg on day 1, followed by oral paclitaxel (Taxol) 160 mg+CsA 700 mg on day 8 (group I) or vice versa (group II). Patients received paclitaxel (Taxol) 160 mg as 3-h infusion on day 15. The median (range) area under the plasma concentration-time curve of paclitaxel was 2.06 (1.15-3.47) microg h ml(-1) and 1.97 (0.58-3.22) microg h ml(-1) after oral administration of SMEOF#3 and Taxol, respectively, and 4.69 (3.90-6.09) microg h ml(-1) after intravenous Taxol. Oral SMEOF#3 resulted in a lower median T(max) of 2.0 (0.5-2.0) h than orally applied Taxol (T(max)=4.0 (0.8-6.1) h, P=0.02). The median apparent bioavailability of paclitaxel was 40 (19-83)% and 55 (9-70)% for the oral SMEOF#3 and oral Taxol formulation, respectively. Oral paclitaxel administered as SMEOF#3 or Taxol was safe and well tolerated by the patients. Remarkably, the SMEOF#3 formulation resulted in a significantly lower T(max) than orally applied Taxol, probably due to the excipients in the SMEOF#3 formulation resulting in a higher absorption rate of paclitaxel.
British Journal of Cancer 10/2006; 95(6):729-34. · 5.08 Impact Factor