title: Cetuximab increases concentrations of irinotecan and of its active metabolite SN-38 in plasma and tumour of human colorectal carcinoma-bearing mice.
abstract: 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.
authors.affiliation: Laboratory of Pharmacology, Service Pharmacie, Hôpital Paul Brousse AP-HP, 14 avenue Paul Vaillant-Couturier, 94800, Villejuif, France; UPRES EA 4123 Faculty of Pharmaceutical Sciences, Université Paris Sud XI, 5 rue Jean-Baptiste Clément, 92296, Châtenay-Malabry cedex, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Chu
authors.forename: Chadi
authors.initials: C
authors.lastname: Abbara
authors.forename: Mahamadou
authors.initials: M
authors.lastname: Tandia
authors.forename: Mélanie
authors.initials: M
authors.lastname: Polrot
authors.forename: Patrick
authors.initials: P
authors.lastname: Gonin
authors.forename: Robert
authors.initials: R
authors.lastname: Farinotti
authors.forename: Laurence
authors.initials: L
authors.lastname: Bonhomme-Faivre
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors; D000284:Administration, Oral; D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics / Q000494:pharmacology; D019540:Area Under Curve; D001692:Biological Transport / Q000187:drug effects; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D000068818:Cetuximab; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D004347:Drug Interactions; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005260:Female; D006801:Humans; D000077146:Irinotecan; D051379:Mice; D008819:Mice, Nude; D014018:Tissue Distribution; D023041:Xenograft Model Antitumor Assays
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D061067:Antibodies, Monoclonal, Humanized; D000077146:Irinotecan; D000068818:Cetuximab; D002166:Camptothecin
keywords: P-glycoprotein; cetuximab; irinotecan; pharmacokinetics