Irinotecan

Irinotecan

Error creating thumbnail: File missing
Clinical data
Pregnancy category	D (Au, U.S.)
Routes of administration	Intravenous
ATC code	L01XX19 (WHO)
Legal status
Legal status	POM (UK), ℞-only (U.S.)
Pharmacokinetic data
Bioavailability	NA
Metabolism	Hepatic glucuronidation
Elimination half-life	6 to 12 hours
Excretion	Biliary and renal
Identifiers
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
CAS Number	100286-90-6
PubChem CID	3750
DrugBank	APRD00579
E number	{{#property:P628}}
ECHA InfoCard	{{#property:P2566}}
Chemical and physical data
Formula	C33H38N4O6
Molar mass	586.678 g/mol 677.185 g/mol (hydrochloride)

WikiDoc Resources for Irinotecan
Articles
Most recent articles on Irinotecan Most cited articles on Irinotecan Review articles on Irinotecan Articles on Irinotecan in N Eng J Med, Lancet, BMJ
Media
Powerpoint slides on Irinotecan Images of Irinotecan Photos of Irinotecan Podcasts & MP3s on Irinotecan Videos on Irinotecan
Evidence Based Medicine
Cochrane Collaboration on Irinotecan Bandolier on Irinotecan TRIP on Irinotecan
Clinical Trials
Ongoing Trials on Irinotecan at Clinical Trials.gov Trial results on Irinotecan Clinical Trials on Irinotecan at Google
Guidelines / Policies / Govt
US National Guidelines Clearinghouse on Irinotecan NICE Guidance on Irinotecan NHS PRODIGY Guidance FDA on Irinotecan CDC on Irinotecan
Books
Books on Irinotecan
News
Irinotecan in the news Be alerted to news on Irinotecan News trends on Irinotecan
Commentary
Blogs on Irinotecan
Definitions
Definitions of Irinotecan
Patient Resources / Community
Patient resources on Irinotecan Discussion groups on Irinotecan Patient Handouts on Irinotecan Directions to Hospitals Treating Irinotecan Risk calculators and risk factors for Irinotecan
Healthcare Provider Resources
Symptoms of Irinotecan Causes & Risk Factors for Irinotecan Diagnostic studies for Irinotecan Treatment of Irinotecan
Continuing Medical Education (CME)
CME Programs on Irinotecan
International
Irinotecan en Espanol Irinotecan en Francais
Business
Irinotecan in the Marketplace Patents on Irinotecan
Experimental / Informatics
List of terms related to Irinotecan

Overview

Irinotecan is a chemotherapy agent that is a topoisomerase 1 inhibitor. Chemically, it is a semisynthetic analogue of the natural alkaloid camptothecin.

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

Irinotecan was first introduced in Japan by the Pharmaceutical arm of Yakult Honsha as Campto®. In 1994, it received accelerated FDA approval in the United States, where it is now marketed by Pfizer as Camptosar®. It is also known as CPT-11.

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.

Side effects

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

Diarrhea

Irinotecan-associated diarrhea is severe and clinically significant, sometimes leading severe dehydration requiring hospitalization or intensive care unit admission. This side effect is managed with the aggressive use of antidiarrheals such as loperamide or Lomotil 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. While the bone marrow, where neutrophils are made, cranks up production to compensate, the patient may experience a period of neutropenia, that is, a clinical lack of neutrophils in the blood.

Pharmacogenomics

Irinotecan is converted by an enzyme into its active metabolite SN-38, which is in turn inactivated by the enzyme UGT1A1. People with variants of the UGT1A1 called TA₇, also known as the *28 variant, express fewer UGT1A1 enzymes in their liver. During chemotherapy, these patients 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 diarrhea and neutropenia .

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 .

In 2005, the FDA made changes to the labelling of irinotecan to add pharmacogenomics recommendations that patients with polymorphisms in UGT1A1 gene, specifically the *28 variant, should perhaps receive reduced drug doses. Irinotecan is one of the first widely-used chemotherapy agents that is dosed for each patient according to his genotype.

See also

• Camptothecin
• Topotecan (Hycamtin®)
• Pharmacogenomics

External links

• Pfizer website
• Irinotecan Pathway on PharmGKB