Irinotecan pathway (WP229)

Homo sapiens

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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] Proteins on this pathway have targeted assays available via the [https://assays.cancer.gov/available_assays?wp_id=WP229 CPTAC Assay Portal]

Authors

Thomas Kelder , Alex Pico , Kristina Hanspers , Martijn Van Iersel , Daniela Digles , Egon Willighagen , Denise Slenter , and Eric Weitz

Activity

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Cited In

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Organisms

Homo sapiens

Communities

CPTAC

Annotations

Disease Ontology

cancer neutropenia diarrhea

Cell Type Ontology

enterocyte hepatocyte

Pathway Ontology

irinotecan drug pathway

Participants
Query Drugst.One

Label Type Compact URI Comment
SN-38G Metabolite chebi:8990
Irinotecan Metabolite chebi:80630
SN-38 Metabolite chebi:8988
NPC Metabolite pubchem.compound:11756356 AKA 7-ethyl-10-(4-amino-1-piperidino) carbonyloxycamptothecin (NPC)]
APC Metabolite pubchem.compound:10077584
UGT1A10 GeneProduct ncbigene:54575
ABCC2 GeneProduct ncbigene:1244
CES2 GeneProduct ncbigene:8824
CES1 GeneProduct ncbigene:1066
CYP3A4 GeneProduct ncbigene:1576
BCHE GeneProduct ncbigene:590
ABCC1 GeneProduct ncbigene:4363
UGT1A9 GeneProduct ncbigene:54600
UGT1A1 GeneProduct ncbigene:54658
CYP3A5 GeneProduct ncbigene:1577
ABCG2 GeneProduct ncbigene:9429
SLCO1B1 GeneProduct ncbigene:10599

References

  1. 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. Iyer L, King CD, Whitington PF, Green MD, Roy SK, Tephly TR, et al. J Clin Invest. 1998 Feb 15;101(4):847–54. PubMed Europe PMC Scholia
  2. The anticancer prodrug CPT-11 is a potent inhibitor of acetylcholinesterase but is rapidly catalyzed to SN-38 by butyrylcholinesterase. Morton CL, Wadkins RM, Danks MK, Potter PM. Cancer Res. 1999 Apr 1;59(7):1458–63. PubMed Europe PMC Scholia
  3. ATP-Dependent efflux of CPT-11 and SN-38 by the multidrug resistance protein (MRP) and its inhibition by PAK-104P. Chen ZS, Furukawa T, Sumizawa T, Ono K, Ueda K, Seto K, et al. Mol Pharmacol. 1999 May;55(5):921–8. PubMed Europe PMC Scholia
  4. Metabolism of irinotecan (CPT-11) by CYP3A4 and CYP3A5 in humans. Santos A, Zanetta S, Cresteil T, Deroussent A, Pein F, Raymond E, et al. Clin Cancer Res. 2000 May;6(5):2012–20. PubMed Europe PMC Scholia
  5. A new metabolite of irinotecan in which formation is mediated by human hepatic cytochrome P-450 3A4. Sai K, Kaniwa N, Ozawa S, Sawada JI. Drug Metab Dispos. 2001 Nov;29(11):1505–13. PubMed Europe PMC Scholia
  6. UGT1A1*28 polymorphism as a determinant of irinotecan disposition and toxicity. Iyer L, Das S, Janisch L, Wen M, Ramírez J, Karrison T, et al. Pharmacogenomics J. 2002;2(1):43–7. PubMed Europe PMC Scholia
  7. Common human UGT1A polymorphisms and the altered metabolism of irinotecan active metabolite 7-ethyl-10-hydroxycamptothecin (SN-38). Gagné JF, Montminy V, Belanger P, Journault K, Gaucher G, Guillemette C. Mol Pharmacol. 2002 Sep;62(3):608–17. PubMed Europe PMC Scholia
  8. Functional characterization of human UDP-glucuronosyltransferase 1A9 variant, D256N, found in Japanese cancer patients. Jinno H, Saeki M, Saito Y, Tanaka-Kagawa T, Hanioka N, Sai K, et al. J Pharmacol Exp Ther. 2003 Aug;306(2):688–93. PubMed Europe PMC Scholia
  9. Differential effects of the breast cancer resistance protein on the cellular accumulation and cytotoxicity of 9-aminocamptothecin and 9-nitrocamptothecin. Rajendra R, Gounder MK, Saleem A, Schellens JHM, Ross DD, Bates SE, et al. Cancer Res. 2003 Jun 15;63(12):3228–33. PubMed Europe PMC Scholia
  10. 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
  11. 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
  12. Haplotype analysis of ABCB1/MDR1 blocks in a Japanese population reveals genotype-dependent renal clearance of irinotecan. Sai K, Kaniwa N, Itoda M, Saito Y, Hasegawa R, Komamura K, et al. Pharmacogenetics. 2003 Dec;13(12):741–57. PubMed Europe PMC Scholia
  13. 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. Nozawa T, Minami H, Sugiura S, Tsuji A, Tamai I. Drug Metab Dispos. 2005 Mar;33(3):434–9. PubMed Europe PMC Scholia