C. Jamois(1,2,3), E. Comets(3), L. Bonhomme-Faivre(1,2) and F. Mentré(3).
Laboratoire de Pharmacologie, Service Pharmacie, Hôpital Paul Brousse, Assistance Publique des Hôpitaux de Paris (APHP), Villejuif, France (1); Unité Propre de Recherche de l’Enseignement Supérieur 2706, Barrière et passage des médicaments, Faculté de Pharmacie de Chatenay Malabry-Paris XI, France (2); Département d’épidémiologie, biostatistiques et recherche clinique, Hôpital Bichat-Claude-Bernard, APHP, Paris, France (3)
Objectives: Paclitaxel is a potent anticancer drug with proven activity against a broad range of human malignancies, including ovarian and breast cancer and non-small cell lung carcinoma. Its oral bioavailability is low and limits extensive use of oral administration.
Intestinal P-glycoprotein (P-gp) is held responsible of the poor bioavailability in vivo, because it transports paclitaxel towards the extracellular matrix, limiting its absorption from the intestinal lumen.
Recombinant interleukin-2 is known to induce a decrease in the protein expression of intestinal P-gp and in the level of CYP-450 in vivo in mice, which is directly related to a decrease in intestinal P-gp activity and to a suppression of hepatic drug metabolism. Those two last points can greatly enhance the oral bioavailability of paclitaxel.
To further study on the feasibility of a clinically effective oral formulation of paclitaxel, it was investigated in our present study whether a 3-day pre-treatment with intraperitoneal rIL2 had a pharmacokinetic effect on paclitaxel profile given per os in Swiss mice.
Materials and methods: 96 mice were allocated to two groups receiving either paclitaxel alone (10 mg/kg by oral route) or rIL2 (16.5 µg twice daily from day 1 to day 3) and were given paclitaxel on day 4 (10 mg/kg by oral route).
Plasma concentrations were measured by High Performance Liquid Chromatography after solid-liquid phase extraction.
Pharmacokinetic profiles were analysed first by the Bailer method, and then using a compartmental approach with software R (freeware equivalent of the statistical language Splus, library nls2).
Results: A complex absorption of paclitaxel has been revealed. The Bailer method showed that the mean AUC values over 0 to 24 hrs were not significantly different in the two groups, but the AUC over 0 to 0.5 hrs were significantly higher in the pre-treated group.
The compartmental analysis has confirmed these results. In the final model, the fraction of drug absorbed during the first phase, has increased significantly in group pre-treated by rIL2, which might be due to the inhibitory effect of rIL2 on intestinal P-gp, whereas the elimination rate constant (Kel) remained the same across both groups.
Conclusion: This pharmacokinetic study showed that, a 3 day pre-treatment with rIL2 is able to increase paclitaxel absorption for 15 minutes following an oral input of paclitaxel but elimination is not modified. Recombinant interleukin-2 could enhance its oral bioavailability.
Reference: PAGE 12 (2003) Abstr 370 [www.page-meeting.org/?abstract=370]
Poster: poster