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| {{Drugbox| | | {{Details0|Irinotecan hydrochloride (Camptosar)}} |
| |IUPAC_name = (''S'')-4,11-diethyl-3,4,12,14-tetrahydro-4-hydroxy-<br>3,14-dioxo1''H''-pyrano[3’,4’:6,7]-indolizino[1,2-b]quinolin-<br>9-yl-[1,4’bipiperidine]-1’-carboxylate
| | {{Details0|Irinotecan hydrochloride (Onivyde)}} |
| | image = irinotecan.svg
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| | width = 240px
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| | CAS_number=100286-90-6
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| | ATC_prefix=L01
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| | ATC_suffix=XX19
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| | PubChem=3750
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| | DrugBank=APRD00579
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| | C = 33 |H = 38 |N = 4 |O = 6
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| | molecular_weight = 586.678 [[Gram|g]]/[[Mole (unit)|mol]]<br>677.185 g/mol ([[hydrochloride]])
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| | bioavailability= NA
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| | metabolism = [[Liver|Hepatic]] [[glucuronidation]]
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| | elimination_half-life= 6 to 12 [[hour]]s
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| | excretion = Biliary and [[Kidney|renal]]
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| | pregnancy_category = D <small>([[Australia|Au]], [[United States|U.S.]])</small>
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| | legal_status = [[Prescription drug|POM]] <small>([[United Kingdom|UK]])</small>, ℞-only <small>(U.S.)</small>
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| | routes_of_administration= [[Intravenous therapy|Intravenous]]
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| }}
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| {{SI}}
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| {{EH}}
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| ==Overview==
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| '''Irinotecan''' is a chemotherapy agent that is a [[Type I topoisomerase|topoisomerase 1]] [[Enzyme inhibitor|inhibitor]]. Chemically, it is a semisynthetic analogue of the natural alkaloid [[camptothecin]].
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| 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.
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| Irinotecan was first introduced in Japan by the Pharmaceutical arm of [[Yakult|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.
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| ==Mechanism==
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| Irinotecan is activated by hydrolysis to SN-38, an inhibitor of topoisomerase I. This is then inactivated by [[glucuronidation]] by [[UGT1A1|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.
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| ==Side effects==
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| The most significant adverse effects of irinotecan are severe diarrhea and extreme suppression of the immune systems.
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| ===Diarrhea===
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| 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.
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| ===Immunosuppression===
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| The immune system is adversely impacted by irinotecan. This is reflected in dramatically lowered [[white blood cell]] counts in the blood, in particular the [[neutrophil|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.
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| ==Pharmacogenomics==
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| 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 TA<sub>7</sub>, 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 <ref> Journal of Clinical Oncology, Vol 22, No 8 April 15, 2004: pp. 1382-1388</ref>.
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| 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
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| <ref name="Innocenti2004">{{
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| cite journal
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| |url=http://www.jco.org/cgi/content/abstract/22/8/1382
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| |author=Innocenti F et al
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| |journal=[[Journal of Clinical Oncology]]
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| |title=Genetic Variants in the UDP-glucuronosyltransferase 1A1 Gene Predict the Risk of Severe Neutropenia of Irinotecan
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| |year = 2004
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| |month = Apr
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| |volume = 22
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| |issue = 8
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| |pages = 1382-88
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| |id = PMID 15007088
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| }}</ref>. | |
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| 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<ref name="ODwyer2006">{{
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| cite journal
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| |url=http://www.jco.org/cgi/content/full/24/28/4534
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| |author=O'Dwyer PJ, Catalano RP
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| |journal=[[Journal of Clinical Oncology]] | |
| |title=Uridine Diphosphate Glucuronosyltransferase (UGT) 1A1 and Irinotecan: Practical Pharmacogenomics Arrives in Cancer Therapy
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| |year = 2006
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| |month = Oct
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| |volume = 24
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| |issue = 28
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| |pages = 4534-38
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| |id = PMID 17008691
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| }}</ref>.
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| ==See also==
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| *[[Camptothecin]]
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| *[[Topotecan]] (Hycamtin®)
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| *[[Pharmacogenomics]]
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| == References ==
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| <references/>
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| ==External links==
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| *[http://camptosar.com/products/camptosar.aspx Pfizer website]
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| *[http://www.pharmgkb.org/do/serve?objId=PA2001&objCls=Pathway Irinotecan Pathway on PharmGKB]
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| {{Chemotherapeutic agents}}
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| [[Category:Cancer treatments]]
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| [[Category:Chemotherapeutic agents]]
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| [[Category:Prodrugs]]
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| {{SIB}}
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| [[de:Irinotecan]]
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| [[ja:イリノテカン]]
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| [[zh:愛萊諾迪肯]]
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| [[ru:Иринотекан]]
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| [[fi:Irinotekaani]]
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| {{WH}}
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| {{WikiDoc Sources}}
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