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

Fundam Clin Pharmacol. 2014 Dec;28(6):652-60. doi: 10.1111/fcp.12071. Epub 2014 Apr 16.

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.

Keywords: P-glycoprotein; cetuximab; irinotecan; pharmacokinetics.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / antagonists & inhibitors
  • Administration, Oral
  • Animals
  • Antibodies, Monoclonal, Humanized / pharmacology*
  • Antineoplastic Combined Chemotherapy Protocols / pharmacokinetics
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology
  • Area Under Curve
  • Biological Transport / drug effects
  • Camptothecin / analogs & derivatives*
  • Camptothecin / pharmacokinetics
  • Camptothecin / pharmacology
  • Cetuximab
  • Colorectal Neoplasms / drug therapy*
  • Colorectal Neoplasms / pathology
  • Drug Interactions
  • Drug Resistance, Neoplasm / drug effects
  • Female
  • Humans
  • Irinotecan
  • Mice
  • Mice, Nude
  • Tissue Distribution
  • Xenograft Model Antitumor Assays

Substances

  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Antibodies, Monoclonal, Humanized
  • Irinotecan
  • Cetuximab
  • Camptothecin