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 |
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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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