Cetuximab increases concentrations of irinotecan and of its active metabolite SN-38 in plasma and tumour of human colorectal carcinoma-bearing mice
In: Fundamental and Clinical Pharmacology Fundamental and Clinical Pharmacology, 2014, 28, pp.652-60. ⟨10.1111/fcp.12071⟩; (2014)
Online
unknown
Zugriff:
International audience; In a previous study, we showed that cetuximab, a monoclonal antibody directed towards epidermal growth factor receptor, could inhibit P-glycoprotein (P-gp), an efflux protein of ATP-binding cassette family, and lead to an increased P-gp substrate intracellular concentration. Cetuximab is given with irinotecan to patients with metastasis colorectal cancer who did not respond to irinotecan-based therapy. The mechanism of this successful clinical reversion remains unknown. As irinotecan is a P-gp substrate, we tested here whether cetuximab could modify irinotecan concentration in mice. Therefore, concentrations of irinotecan and of its active metabolite SN-38 were measured by HPLC in plasma and tumour of mice bearing a human colorectal carcinoma xenograft when irinotecan is given orally alone or after a pretreatment with cetuximab. Pharmacokinetic analysis showed no significant modification of irinotecan concentrations but a significant increase (1.7-fold) in SN-38 AUCs in plasma and in tumour after a pretreatment with cetuximab. Those results suggest that cetuximab influence irinotecan distribution into tissues probably due to inhibition of P-gp. As SN-38 is 200-fold more potent than irinotecan, cetuximab could reverse irinotecan resistance by an effect on its active metabolite. Inhibiting SN-38 efflux by P-gp drug transporters in biliary system and tumour can lead to pharmacokinetic modification and a higher anticancer efficacy.
Titel: |
Cetuximab increases concentrations of irinotecan and of its active metabolite SN-38 in plasma and tumour of human colorectal carcinoma-bearing mice
|
---|---|
Autor/in / Beteiligte Person: | Chu, Céline ; Gonin, Patrick ; Farinotti, Robert ; Bonhomme-Faivre, Laurence ; Tandia, Mahamadou ; Abbara, Chadi ; Polrot, Mélanie ; Groupe d'Étude des Interactions Hôte-Pathogène (GEIHP) ; Université d'Angers (UA) |
Link: | |
Quelle: | Fundamental and Clinical Pharmacology Fundamental and Clinical Pharmacology, 2014, 28, pp.652-60. ⟨10.1111/fcp.12071⟩; (2014) |
Veröffentlichung: | HAL CCSD, 2014 |
Medientyp: | unknown |
ISSN: | 1472-8206 (print) |
Schlagwort: |
|
Sonstiges: |
|