Irinotecan pathway (WP124)

Rattus norvegicus

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. Source: [http://www.pharmgkb.org/search/pathway/irinotecan/liver.jsp PharmGkb]

Authors

Thomas Kelder , Daniela Digles , Egon Willighagen , Martina Summer-Kutmon , Denise Slenter , Alex Pico , Eric Weitz , and Amadeo

Activity

last edited

Discuss this pathway

Check for ongoing discussions or start your own.

Cited In

Are you planning to include this pathway in your next publication? See How to Cite and add a link here to your paper once it's online.

Organisms

Rattus norvegicus

Communities

Annotations

Disease Ontology

diarrhea cancer neutropenia

Pathway Ontology

irinotecan drug pathway

Participants

Label Type Compact URI Comment
Irinotecan Metabolite chemspider:54825
Irinotecan Metabolite chebi:80630
SN-38 Metabolite chebi:8988
SN-38G Metabolite chebi:8990
APC Metabolite chebi:80551
Abcc1 GeneProduct ncbigene:24565
Abcg2 GeneProduct ncbigene:312382
Abcc2 GeneProduct ncbigene:25303
Ces2 GeneProduct ncbigene:171118
RGD:621508 GeneProduct ncbigene:29225
CYP3A4 GeneProduct ncbigene:1576
Ugt1a6 GeneProduct ncbigene:113992
Ugt1a1 GeneProduct ncbigene:24861
UGT1A10 GeneProduct ncbigene:54575
CYP3A5 GeneProduct ncbigene:1577
UGT1A9 GeneProduct ncbigene:396552
NPC1 GeneProduct ncbigene:4864
Bche GeneProduct ncbigene:65036

References

  1. UGT pharmacogenomics: implications for cancer risk and cancer therapeutics. Desai AA, Innocenti F, Ratain MJ. Pharmacogenetics. 2003 Aug;13(8):517–23. PubMed Europe PMC Scholia
  2. Irinotecan pathway genotype analysis to predict pharmacokinetics. Mathijssen RHJ, Marsh S, Karlsson MO, Xie R, Baker SD, Verweij J, et al. Clin Cancer Res. 2003 Aug 15;9(9):3246–53. PubMed Europe PMC Scholia