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Cetuximab increases concentrations of irinotecan and of its active metabolite SN ‐38 in plasma and tumour of human colorectal carcinoma‐bearing mice
Author(s) -
Chu Céline,
Abbara Chadi,
Tandia Mahamadou,
Polrot Mélanie,
Gonin Patrick,
Farinotti Robert,
BonhommeFaivre Laurence
Publication year - 2014
Publication title -
fundamental and clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.655
H-Index - 73
eISSN - 1472-8206
pISSN - 0767-3981
DOI - 10.1111/fcp.12071
Subject(s) - irinotecan , cetuximab , sn 38 , colorectal cancer , pharmacokinetics , pharmacology , camptothecin , epidermal growth factor receptor , active metabolite , metabolite , efflux , medicine , chemistry , monoclonal antibody , cancer research , cancer , immunology , antibody , biochemistry
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 AUC s 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.