Active transepithelial transport of irinotecan (CPT-11) and its metabolites by human intestinal Caco-2 cells

Anticancer Drugs. 2001 Jun;12(5):419-32. doi: 10.1097/00001813-200106000-00003.


Irinotecan (CPT-11) is a camptothecin analog with low (about 10--20%) and variable oral bioavailability in animal models. Here, Caco-2 cells were used to evaluate the transepithelial transport of CPT-11 and its metabolites. Caco-2 cells demonstrated significant expression of P-glycoprotein (P-gp), multidrug resistance-associated protein and canalicular multispecific organic anion transporter. Both the lactone and carboxylate forms of CPT-11 and SN-38 were actively transported across the cell monolayers, mainly by the apical-localized P-gp pump. Cellular permeability of CPT-11 at a concentration of 17 microM converted from active to passive-diffusional transport between the 2 and 6 h exposure time points. Antiproliferative effects of CPT-11 were related to permeability of the lactone form, whereas for SN-38 efficacy was dependent on lactone accumulation. Exposure of CPT-11 with cyclosporin A significantly enhanced its efficacy, whereas this was not observed with verapamil and R101933. In contrast, SN-38 efficacy decreased in the presence of P-gp inhibitors due to active transport toward the basolateral side, thereby reducing drug accumulation. Hence, multiple-active transport systems could be demonstrated to be responsible for not only accumulation profiles but also cytotoxic efficacy of CPT-11 and SN-38 in the intestinal Caco-2 cells. It is suggested that CPT-11 might act in a time-dependent manner and that SN-38-mediated cytotoxicity relates to (dose-dependent) lactone kinetics. The results detailed in this report could contribute toward the development of a clinically useful oral formulation of CPT-11 with improved absorption characteristics and suggest that cyclosporin A is a suitable agent for further research of this concept.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / antagonists & inhibitors
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
  • Animals
  • Antineoplastic Agents, Phytogenic / pharmacokinetics*
  • Benzazepines / pharmacology
  • Biological Transport
  • Biotransformation
  • Caco-2 Cells / metabolism*
  • Camptothecin / analogs & derivatives
  • Camptothecin / pharmacokinetics*
  • Cell Survival / drug effects
  • Chromatography, High Pressure Liquid
  • Cyclosporine / pharmacology
  • Humans
  • Intestinal Mucosa / metabolism*
  • Irinotecan
  • Quinolines / pharmacology
  • RNA, Messenger / metabolism
  • Verapamil / pharmacology


  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Antineoplastic Agents, Phytogenic
  • Benzazepines
  • Quinolines
  • RNA, Messenger
  • Irinotecan
  • Cyclosporine
  • Verapamil
  • laniquidar
  • Camptothecin