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]
AKA 7-ethyl-10-(4-amino-1-piperidino) carbonyloxycamptothecin (NPC)]
molecular weight, 558
fd7
d54
cc6
d4c
cb7
bc2
ae6
aa1
a33
aa1
a33
ecb
ac8
e72
e81
ae6
aa1
a33
12181437
PubMed
Common human UGT1A polymorphisms and the altered metabolism of irinotecan active metabolite 7-ethyl-10-hydroxycamptothecin (SN-38).
Mol Pharmacol
2002
Gagné JF
Montminy V
Belanger P
Journault K
Gaucher G
Guillemette C
10815927
PubMed
Metabolism of irinotecan (CPT-11) by CYP3A4 and CYP3A5 in humans.
Clin Cancer Res
2000
Santos A
Zanetta S
Cresteil T
Deroussent A
Pein F
Raymond E
Vernillet L
Risse ML
Boige V
Gouyette A
Vassal G
11602529
PubMed
A new metabolite of irinotecan in which formation is mediated by human hepatic cytochrome P-450 3A4.
Drug Metab Dispos
2001
Sai K
Kaniwa N
Ozawa S
Sawada JI
12730278
PubMed
Functional characterization of human UDP-glucuronosyltransferase 1A9 variant, D256N, found in Japanese cancer patients.
J Pharmacol Exp Ther
2003
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
cancer
DOID:162
Disease
15608127
PubMed
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
Nozawa T
Minami H
Sugiura S
Tsuji A
Tamai I
14646693
PubMed
Haplotype analysis of ABCB1/MDR1 blocks in a Japanese population reveals genotype-dependent renal clearance of irinotecan.
Pharmacogenetics
2003
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
enterocyte
CL:0000584
Cell Type
11990381
PubMed
UGT1A1*28 polymorphism as a determinant of irinotecan disposition and toxicity.
Pharmacogenomics J
2002
Iyer L
Das S
Janisch L
Wen M
Ramírez, J
Karrison T
Fleming GF
Vokes EE
Schilsky RL
Ratain MJ
12960109
PubMed
Irinotecan pathway genotype analysis to predict pharmacokinetics.
Clin Cancer Res
2003
Mathijssen RH
Marsh S
Karlsson MO
Xie R
Baker SD
Verweij J
Sparreboom A
McLeod HL
neutropenia
DOID:1227
Disease
irinotecan drug pathway
PW:0001224
Pathway Ontology
diarrhea
DOID:13250
Disease
12893990
PubMed
UGT pharmacogenomics: implications for cancer risk and cancer therapeutics.
Pharmacogenetics
2003
Desai AA
Innocenti F
Ratain MJ
12810652
PubMed
Differential effects of the breast cancer resistance protein on the cellular accumulation and cytotoxicity of 9-aminocamptothecin and 9-nitrocamptothecin.
Cancer Res
2003
Rajendra R
Gounder MK
Saleem A
Schellens JH
Ross DD
Bates SE
Sinko P
Rubin EH
10220571
PubMed
ATP-Dependent efflux of CPT-11 and SN-38 by the multidrug resistance protein (MRP) and its inhibition by PAK-104P.
Mol Pharmacol
1999
Chen ZS
Furukawa T
Sumizawa T
Ono K
Ueda K
Seto K
Akiyama SI
hepatocyte
CL:0000182
Cell Type
9466980
PubMed
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
Iyer L
King CD
Whitington PF
Green MD
Roy SK
Tephly TR
Coffman BL
Ratain MJ
10197614
PubMed
The anticancer prodrug CPT-11 is a potent inhibitor of acetylcholinesterase but is rapidly catalyzed to SN-38 by butyrylcholinesterase.
Cancer Res
1999
Morton CL
Wadkins RM
Danks MK
Potter PM