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Irinotecan

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Title: Irinotecan  
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Subject: List of chemotherapeutic agents, Camptothecin, Chemotherapy regimen, Topoisomerase inhibitor, Pfizer
Collection: Lactams, Lactones, Pfizer, Piperidines, Prodrugs, Pyranoindolizinoquinolines, Topoisomerase Inhibitors
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Irinotecan

Irinotecan
Systematic (IUPAC) name
(S)-4,11-diethyl-3,4,12,14-tetrahydro-4-hydroxy-
3,14-dioxo1H-pyrano[3’,4’:6,7]-indolizino[1,2-b]quinolin-
9-yl-[1,4’bipiperidine]-1’-carboxylate
Clinical data
Trade names Camptosar
AHFS/Drugs.com
MedlinePlus
Pregnancy
category
  • D (Australia, United States)
Legal status
  • POM (UK), ℞-only (U.S.)
Routes of
administration
Intravenous
Pharmacokinetic data
Bioavailability NA
Metabolism Hepatic glucuronidation
Biological half-life 6 to 12 hours
Excretion Biliary and renal
Identifiers
CAS Registry Number  Y
ATC code L01
PubChem CID:
IUPHAR/BPS
DrugBank  Y
ChemSpider  Y
UNII  Y
KEGG  Y
ChEMBL  Y
Chemical data
Formula C33H38N4O6
Molecular mass 586.678 g/mol (Irinotecan)
623.139 g/mol (Irinotecan hydrochloride)
677.185 g/mol (Irinotecan hydrochloride trihydrate)
 Y   

Irinotecan (Camptosar, Pfizer; Campto) is a drug used for the treatment of cancer.

Irinotecan prevents DNA from unwinding by inhibition of topoisomerase 1.[1] In chemical terms, it is a semisynthetic analogue of the natural alkaloid camptothecin.

Its main use is in colon cancer, in particular, in combination with other chemotherapy agents. This includes the regimen FOLFIRI, which consists of infusional 5-fluorouracil, leucovorin, and irinotecan.

Irinotecan received accelerated approval by the U.S. Food and Drug Administration (FDA) in 1996[2] and full approval in 1998.[3] During development, it was known as CPT-11.

Contents

  • Mechanism 1
  • Interactive pathway map 2
  • Side-effects 3
    • Diarrhea 3.1
    • Immunosuppression 3.2
  • Pharmacogenomics 4
    • *28 variant patients 4.1
  • Research 5
  • Synthesis 6
  • See also 7
  • References 8
  • External links 9

Mechanism

Irinotecan is activated by hydrolysis to SN-38, an inhibitor of topoisomerase I. This is then inactivated by glucuronidation by uridine diphosphate glucoronosyltransferase 1A1 (UGT1A1). The inhibition of topoisomerase I by the active metabolite SN-38 eventually leads to inhibition of both DNA replication and transcription.

Interactive pathway map

Click on genes, proteins and metabolites below to link to respective articles. [§ 1]

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Irinotecan Pathway edit
  1. ^ The interactive pathway map can be edited at WikiPathways: "IrinotecanPathway_WP46359". 

Side-effects

The most significant adverse effects of irinotecan are severe diarrhea and extreme suppression of the immune system.

Diarrhea

Irinotecan-associated diarrhea is severe and clinically significant, sometimes leading to severe dehydration requiring hospitalization or intensive care unit admission. This side-effect is managed with the aggressive use of antidiarrheals such as loperamide or co-phenotrope with the first loose bowel movement.

Immunosuppression

The immune system is adversely impacted by irinotecan. This is reflected in dramatically lowered white blood cell counts in the blood, in particular the neutrophils. The patient may experience a period of neutropenia (a clinically significant decrease of neutrophils in the blood) while the bone marrow increases white cell production to compensate.

Pharmacogenomics

Irinotecan is converted by an enzyme into its active metabolite SN-38, which is in turn inactivated by the enzyme UGT1A1 by glucuronidation.

*28 variant patients

People with variants of the UGT1A1 called TA7, also known as the "*28 variant", express fewer UGT1A1 enzymes in their liver and often suffer from Gilbert's syndrome. During chemotherapy, they effectively receive a larger than expected dose because their bodies are not able to clear irinotecan as fast as others. In studies this corresponds to higher incidences of severe neutropenia and diarrhea.[4]

In 2004, a clinical study was performed that both validated prospectively the association of the *28 variant with greater toxicity and the ability of genetic testing in predicting that toxicity before chemotherapy administration.[4]

In 2005, the FDA made changes to the labeling of irinotecan to add pharmacogenomics recommendations, such that irinotecan recipients with a homozygous (both of the two gene copies) polymorphism in UGT1A1 gene, to be specific, the *28 variant, should be considered for reduced drug doses.[5] Irinotecan is one of the first widely used chemotherapy agents that is dosed according to the recipient's genotype.[6]

Research

Recently it was shown that antitumor activity of irinotecan against glioblastoma can be enhanced by co-treatment with statins.[7] Similarly, it was shown that berberine may enhance chemosensitivity to irinotecan in colon cancer cells.[8]

Synthesis

Irinotecan synthesis:[9]

See also

References

  1. ^ Pommier, Y.; Leo, E.; Zhang, H.; Marchand, C. (2010). "DNA topoisomerases and their poisoning by anticancer and antibacterial drugs". Chem. Biol 17: 421–433. 
  2. ^ New York Times Article http://www.nytimes.com/1996/06/18/science/new-cancer-drug-approved.html
  3. ^ FDA Review Letter http://www.accessdata.fda.gov/drugsatfda_docs/appletter/1998/20571s8ltr.pdf
  4. ^ a b Innocenti F, Undevia SD, Iyer L, et al. (April 2004). "Genetic variants in the UDP-glucuronosyltransferase 1A1 gene predict the risk of severe neutropenia of irinotecan". J. Clin. Oncol. 22 (8): 1382–8.  
  5. ^ Camptosar® irinotecan hydrochloride injection August 2010 http://labeling.pfizer.com/ShowLabeling.aspx?id=533
  6. ^ O'Dwyer PJ, Catalano RB (October 2006). "Uridine diphosphate glucuronosyltransferase (UGT) 1A1 and irinotecan: practical pharmacogenomics arrives in cancer therapy". J. Clin. Oncol. 24 (28): 4534–8.  
  7. ^ Jiang PF (Jan 2014). "Novel anti-glioblastoma agents and therapeutic combinations identified from a collection of FDA approved drugs.". J Transl Med. 12.  
  8. ^ Yu M (Jan 2014). "Berberine enhances chemosensitivity to irinotecan in colon cancer via inhibition of NF-κB". J Mol Med Rep 9 (1): 249–54.  
  9. ^ Sawada, S.; Okajima, S.; Aiyama, R.; Nokata, K. I.; Furuta, T.; Yokokura, T.; Sugino, E.; Yamaguchi, K.; Miyasaka, T. (1991). "Synthesis and Antitumor Activity of 20(S)-Camptothecin Derivatives: Carbamate-Linked, Water-Soluble Derivatives of 7-Ethyl-10-hydroxycamptothecin". Chemical & Pharmaceutical Bulletin 39 (6): 1446.  
  10. ^ DNA Topoisomerases and Cancer. Yves Pommier, Editor. Human Press. 2012

External links

  • Pfizer website
  • Irinotecan Pathway on PharmGKB
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