Pharmacokinetic and pharmacogenetic determinants of the activity and toxicity of irinotecan in metastatic colorectal cancer patients

Br J Cancer. 2008 Oct 21;99(8):1239-45. doi: 10.1038/sj.bjc.6604673. Epub 2008 Sep 16.


This study aims at establishing relationships between genetic and non-genetic factors of variation of the pharmacokinetics of irinotecan and its metabolites; and also at establishing relationships between the pharmacokinetic or metabolic parameters and the efficacy and toxicity of irinotecan. We included 49 patients treated for metastatic colorectal cancer with a combination of 5-fluorouracil and irinotecan; a polymorphism in the UGT1A1 gene (TA repeat in the TATA box) and one in the CES2 gene promoter (830C>G) were studied as potential markers for SN-38 glucuronidation and irinotecan activation, respectively; and the potential activity of CYP3A4 was estimated from cortisol biotransformation into 6beta-hydroxycortisol. No pharmacokinetic parameter was directly predictive of clinical outcome or toxicity. The AUCs of three important metabolites of irinotecan, SN-38, SN-38 glucuronide and APC, were tentatively correlated with patients' pretreatment biological parameters related to drug metabolism (plasma creatinine, bilirubin and liver enzymes, and blood leukocytes). SN-38 AUC was significantly correlated with blood leukocytes number and SN-38G AUC was significantly correlated with plasma creatinine, whereas APC AUC was significantly correlated with plasma liver enzymes. The relative extent of irinotecan activation was inversely correlated with SN-38 glucuronidation. The TATA box polymorphism of UGT1A1 was significantly associated with plasma bilirubin levels and behaved as a significant predictor for neutropoenia. The level of cortisol 6beta-hydroxylation predicted for the occurrence of diarrhoea. All these observations may improve the routine use of irinotecan in colorectal cancer patients. UGT1A1 genotyping plus cortisol 6beta-hydroxylation determination could help to determine the optimal dose of irinotecan.

Publication types

  • Clinical Trial

MeSH terms

  • Adult
  • Aged
  • Antineoplastic Agents, Phytogenic / blood
  • Antineoplastic Agents, Phytogenic / pharmacology*
  • Area Under Curve
  • Camptothecin / analogs & derivatives*
  • Camptothecin / blood
  • Camptothecin / pharmacology
  • Carboxylesterase / genetics
  • Chromatography, High Pressure Liquid
  • Colonic Neoplasms / drug therapy*
  • Colonic Neoplasms / genetics*
  • Female
  • Glucuronides / blood
  • Glucuronosyltransferase / genetics
  • Humans
  • Irinotecan
  • Male
  • Middle Aged
  • Polymerase Chain Reaction
  • Polymorphism, Genetic
  • Promoter Regions, Genetic / genetics


  • 7-ethyl-10-hydroxycamptothecin glucuronide
  • Antineoplastic Agents, Phytogenic
  • Glucuronides
  • Irinotecan
  • UGT1A1 enzyme
  • Glucuronosyltransferase
  • CES2 protein, human
  • Carboxylesterase
  • Camptothecin