title: Pharmacokinetic and pharmacogenetic determinants of the activity and toxicity of irinotecan in metastatic colorectal cancer patients.
abstract: 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.
authors.affiliation: Laboratoire d'Oncopharmacologie, Centre Paul-Papin, 2 rue Moll, Angers 49000, France.
authors.forename: E
authors.initials: E
authors.lastname: Rouits
authors.forename: V
authors.initials: V
authors.lastname: Charasson
authors.forename: A
authors.initials: A
authors.lastname: Pétain
authors.forename: M
authors.initials: M
authors.lastname: Boisdron-Celle
authors.forename: J-P
authors.initials: JP
authors.lastname: Delord
authors.forename: M
authors.initials: M
authors.lastname: Fonck
authors.forename: A
authors.initials: A
authors.lastname: Laurand
authors.forename: A-L
authors.initials: AL
authors.lastname: Poirier
authors.forename: A
authors.initials: A
authors.lastname: Morel
authors.forename: E
authors.initials: E
authors.lastname: Chatelut
authors.forename: J
authors.initials: J
authors.lastname: Robert
authors.forename: E
authors.initials: E
authors.lastname: Gamelin
mesh_terms: D000328:Adult; D000368:Aged; D000972:Antineoplastic Agents, Phytogenic / Q000097:blood / Q000494:pharmacology*; D019540:Area Under Curve; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000097:blood / Q000494:pharmacology; D043182:Carboxylesterase / Q000235:genetics; D002851:Chromatography, High Pressure Liquid; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D005260:Female; D020719:Glucuronides / Q000097:blood; D014453:Glucuronosyltransferase / Q000235:genetics; D006801:Humans; D000077146:Irinotecan; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic / Q000235:genetics; D000099148:UGT1A1 Enzyme
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D002166:Camptothecin; D043182:Carboxylesterase; D020719:Glucuronides; D014453:Glucuronosyltransferase; D000077146:Irinotecan; D000099148:UGT1A1 Enzyme; C441475:7-ethyl-10-hydroxycamptothecin glucuronide; C517204:CES2 protein, human
references.citation: J Clin Oncol. 2003 Jul 1;21(13):2481-5
references.pmid: 12829666
references.citation: Adv Drug Deliv Rev. 2002 Nov 18;54(10):1271-94
references.pmid: 12406645
references.citation: J Clin Oncol. 2005 Jan 20;23(3):502-9
references.pmid: 15659495
references.citation: Clin Cancer Res. 2003 Aug 15;9(9):3246-53
references.pmid: 12960109
references.citation: J Clin Oncol. 1999 Jun;17(6):1897-905
references.pmid: 10561231
references.citation: Drugs. 1997 Apr;53(4):593-607
references.pmid: 9098662
references.citation: Clin Cancer Res. 2005 Oct 1;11(19 Pt 1):6901-7
references.pmid: 16203781
references.citation: J Natl Cancer Inst. 2004 Nov 3;96(21):1585-92
references.pmid: 15523087
references.citation: Eur J Cancer. 1999 Sep;35(9):1343-7
references.pmid: 10658525
references.citation: Clin Cancer Res. 2007 Jun 1;13(11):3269-75
references.pmid: 17510208
references.citation: Drug Metab Dispos. 1998 Aug;26(8):769-74
references.pmid: 9698291
references.citation: N Engl J Med. 2004 Jul 22;351(4):337-45
references.pmid: 15269313
references.citation: Pharmacol Ther. 1995;68(2):269-96
references.pmid: 8719971
references.citation: Cancer Res. 1998 Feb 1;58(3):468-72
references.pmid: 9458091
references.citation: Clin Cancer Res. 2004 Aug 1;10(15):5151-9
references.pmid: 15297419
references.citation: Curr Oncol Rep. 2004 Jan;6(1):42-8
references.pmid: 14664760
references.citation: J Clin Oncol. 2000 Aug;18(16):2938-47
references.pmid: 10944126
references.citation: J Clin Pharmacol. 2007 Jan;47(1):78-86
references.pmid: 17192505
references.citation: Pharmacogenomics J. 2002;2(1):43-7
references.pmid: 11990381
references.citation: Lancet. 2000 Mar 25;355(9209):1041-7
references.pmid: 10744089
references.citation: Bull Cancer. 2005 Jan;92(1):7-11
references.pmid: 15689322
references.citation: Ann Oncol. 2005 Mar;16(3):481-8
references.pmid: 15718248
references.citation: J Clin Oncol. 2000 Jun;18(11):2301-8
references.pmid: 10829051
references.citation: Clin Cancer Res. 1997 Aug;3(8):1261-6
references.pmid: 9815808
references.citation: J Clin Oncol. 1995 Jan;13(1):210-21
references.pmid: 7799022
references.citation: J Clin Oncol. 1996 Oct;14(10):2688-95
references.pmid: 8874328
references.citation: Jpn J Cancer Res. 1995 Jan;86(1):101-10
references.pmid: 7737901
references.citation: Cancer Res. 1994 Aug 15;54(16):4347-54
references.pmid: 8044782
references.citation: J Chromatogr B Biomed Appl. 1994 Nov 4;661(1):133-41
references.pmid: 7866541
references.citation: Clin Cancer Res. 2000 Mar;6(3):813-9
references.pmid: 10741701
references.citation: J Chromatogr B Analyt Technol Biomed Life Sci. 2003 Aug 15;793(2):357-66
references.pmid: 12906911
references.citation: Clin Pharmacol Ther. 2004 Dec;76(6):528-35
references.pmid: 15592324
references.citation: Ann Oncol. 1995 Feb;6(2):133-40
references.pmid: 7786821
references.citation: Annu Rev Med. 2005;56:139-56
references.pmid: 15660506
references.citation: J Clin Oncol. 1996 Apr;14(4):1128-35
references.pmid: 8648367
references.citation: J Clin Oncol. 2006 Jul 1;24(19):3061-8
references.pmid: 16809730
references.citation: Clin Cancer Res. 2004 Dec 15;10(24):8341-50
references.pmid: 15623611