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
GenMAPP remarks
Adapted from Pharmgkb (right click for notes)
HomologyConvert
This pathway was inferred from Homo sapiens pathway WP229(r26589) with a 65% conversion rate.
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
Desai AA, Innocenti F, Ratain MJ; ''UGT pharmacogenomics: implications for cancer risk and cancer therapeutics.''; Pharmacogenetics, 2003 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
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