Cetuximab increases concentrations of irinotecan and of its active metabolite SN-38 in plasma and tumour of human colorectal carcinoma-bearing mice

Autor: Céline Chu, Patrick Gonin, Robert Farinotti, Laurence Bonhomme-Faivre, Mahamadou Tandia, Chadi Abbara, Mélanie Polrot
Přispěvatelé: Groupe d'Étude des Interactions Hôte-Pathogène (GEIHP), Université d'Angers (UA)
Jazyk: angličtina
Rok vydání: 2014
Předmět:
Colorectal cancer
[SDV]Life Sciences [q-bio]
Administration
Oral
Mice
Nude
SN-38
Pharmacology
P-glycoprotein
Antibodies
Monoclonal
Humanized
030226 pharmacology & pharmacy
03 medical and health sciences
chemistry.chemical_compound
Mice
0302 clinical medicine
Antineoplastic Combined Chemotherapy Protocols
cetuximab
medicine
Animals
Humans
Pharmacology (medical)
Drug Interactions
Tissue Distribution
Pharmacokinetics
Epidermal growth factor receptor
ATP Binding Cassette Transporter
Subfamily B
Member 1
neoplasms
Active metabolite
irinotecan
Cetuximab
biology
Biological Transport
medicine.disease
Xenograft Model Antitumor Assays
digestive system diseases
3. Good health
Irinotecan
stomatognathic diseases
chemistry
Drug Resistance
Neoplasm
030220 oncology & carcinogenesis
Area Under Curve
biology.protein
Camptothecin
Female
Colorectal Neoplasms
medicine.drug
Zdroj: Fundamental and Clinical Pharmacology
Fundamental and Clinical Pharmacology, 2014, 28, pp.652-60. ⟨10.1111/fcp.12071⟩
ISSN: 1472-8206
Popis: 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.
Databáze: OpenAIRE
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