http://www.pharmgkb.org/search/pathway/irinotecan/liver.jsp# This pathway shows the biotransformation of the chemotherapy prodrug irinotecan to form the active metabolite SN-38, an inhibitor of DNA topoisomerase I. SN-38 is primarily metabolized to the inactive SN-38 glucuronide by UGT1A1, the isoform catalyzing bilirubin glucuronidation. Irinotecan is used in the treatment of metastatic colorectal cancer, small cell lung cancer and several other solid tumors. There is large interpatient variability in response to irinotecan, as well as severe side effects such as diarrhea and neutropenia, which might be explained in part by genetic variation in the metabolic enzymes and transporters depicted here. Well-known variants to effect this pathway are the promoter polymorphic repeat in UGT1A1 (UGT1A1*28) and the 1236C>T polymorphism in ABCB1. While UGT1A1*28 genotype has been associated with toxicity, further evidence is needed to describe the roles of ABCB1 variants in toxicity. The effects of variants in these genes and in the carboxylesterases can be seen by clicking on the yellow-headed arrows which link to primary data from PharmGKB phenotype and genotype studies.
Many of the metabolic enzymes and transporters depicted here are also involved in the pharmacokinetics of other common drugs and xenobiotics, including anticonvulsants, calcium channel blockers, macrolide antibiotics, HIV antivirals, statins and St Johns Wort, and thus co-treatment with a combination of any of these drugs may also impact efficacy and toxicity.
AUTHORS: C.F. Thorn, M.W. Carrillo, J. Ramirez, S. Marsh, E.G. Schuetz, M.E. Dolan, F. Innocenti, M.V. Relling, H.L. McLeod and M.J. Ratain.
DATE POSTED: September 12, 2003
DATE LAST UPDATED: July 12, 2004
Desai AA, Innocenti F, Ratain MJ; ''UGT pharmacogenomics: implications for cancer risk and cancer therapeutics.''; Pharmacogenetics, 2003 PubMedEurope PMCScholia
Sai K, Kaniwa N, Itoda M, Saito Y, Hasegawa R, Komamura K, Ueno K, Kamakura S, Kitakaze M, Shirao K, Minami H, Ohtsu A, Yoshida T, Saijo N, Kitamura Y, Kamatani N, Ozawa S, Sawada J; ''Haplotype analysis of ABCB1/MDR1 blocks in a Japanese population reveals genotype-dependent renal clearance of irinotecan.''; Pharmacogenetics, 2003 PubMedEurope PMCScholia
Jinno H, Saeki M, Saito Y, Tanaka-Kagawa T, Hanioka N, Sai K, Kaniwa N, Ando M, Shirao K, Minami H, Ohtsu A, Yoshida T, Saijo N, Ozawa S, Sawada J; ''Functional characterization of human UDP-glucuronosyltransferase 1A9 variant, D256N, found in Japanese cancer patients.''; J Pharmacol Exp Ther, 2003 PubMedEurope PMCScholia
Nozawa T, Minami H, Sugiura S, Tsuji A, Tamai I; ''Role of organic anion transporter OATP1B1 (OATP-C) in hepatic uptake of irinotecan and its active metabolite, 7-ethyl-10-hydroxycamptothecin: in vitro evidence and effect of single nucleotide polymorphisms.''; Drug Metab Dispos, 2005 PubMedEurope PMCScholia
Iyer L, Das S, Janisch L, Wen M, Ramírez, J, Karrison T, Fleming GF, Vokes EE, Schilsky RL, Ratain MJ; ''UGT1A1*28 polymorphism as a determinant of irinotecan disposition and toxicity.''; Pharmacogenomics J, 2002 PubMedEurope PMCScholia
Sai K, Kaniwa N, Ozawa S, Sawada JI; ''A new metabolite of irinotecan in which formation is mediated by human hepatic cytochrome P-450 3A4.''; Drug Metab Dispos, 2001 PubMedEurope PMCScholia
Rajendra R, Gounder MK, Saleem A, Schellens JH, Ross DD, Bates SE, Sinko P, Rubin EH; ''Differential effects of the breast cancer resistance protein on the cellular accumulation and cytotoxicity of 9-aminocamptothecin and 9-nitrocamptothecin.''; Cancer Res, 2003 PubMedEurope PMCScholia
Santos A, Zanetta S, Cresteil T, Deroussent A, Pein F, Raymond E, Vernillet L, Risse ML, Boige V, Gouyette A, Vassal G; ''Metabolism of irinotecan (CPT-11) by CYP3A4 and CYP3A5 in humans.''; Clin Cancer Res, 2000 PubMedEurope PMCScholia
Mathijssen RH, Marsh S, Karlsson MO, Xie R, Baker SD, Verweij J, Sparreboom A, McLeod HL; ''Irinotecan pathway genotype analysis to predict pharmacokinetics.''; Clin Cancer Res, 2003 PubMedEurope PMCScholia
Morton CL, Wadkins RM, Danks MK, Potter PM; ''The anticancer prodrug CPT-11 is a potent inhibitor of acetylcholinesterase but is rapidly catalyzed to SN-38 by butyrylcholinesterase.''; Cancer Res, 1999 PubMedEurope PMCScholia
Iyer L, King CD, Whitington PF, Green MD, Roy SK, Tephly TR, Coffman BL, Ratain MJ; ''Genetic predisposition to the metabolism of irinotecan (CPT-11). Role of uridine diphosphate glucuronosyltransferase isoform 1A1 in the glucuronidation of its active metabolite (SN-38) in human liver microsomes.''; J Clin Invest, 1998 PubMedEurope PMCScholia
Chen ZS, Furukawa T, Sumizawa T, Ono K, Ueda K, Seto K, Akiyama SI; ''ATP-Dependent efflux of CPT-11 and SN-38 by the multidrug resistance protein (MRP) and its inhibition by PAK-104P.''; Mol Pharmacol, 1999 PubMedEurope PMCScholia
Many of the metabolic enzymes and transporters depicted here are also involved in the pharmacokinetics of other common drugs and xenobiotics, including anticonvulsants, calcium channel blockers, macrolide antibiotics, HIV antivirals, statins and St Johns Wort, and thus co-treatment with a combination of any of these drugs may also impact efficacy and toxicity.
AUTHORS: C.F. Thorn, M.W. Carrillo, J. Ramirez, S. Marsh, E.G. Schuetz, M.E. Dolan, F. Innocenti, M.V. Relling, H.L. McLeod and M.J. Ratain.
DATE POSTED: September 12, 2003
DATE LAST UPDATED: July 12, 2004
Try the New WikiPathways
View approved pathways at the new wikipathways.org.Quality Tags
Ontology Terms
Bibliography
History
External references
DataNodes
Annotated Interactions
No annotated interactions