Pharmacogenetics of irinotecan metabolism and transport: an update.

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Smith NF, Figg WD, Sparreboom A

Pharmacogenetics of irinotecan metabolism and transport: an update.

Toxicol In Vitro. 2006 Mar;20(2):163-75. doi: 10.1016/j.tiv.2005.06.045. Epub 2005 Nov 3.

PubMed ID

16271446 [ View in PubMed

]

Abstract

The anticancer agent irinotecan (CPT-11) is converted to SN-38, which is approximately 100 to 1,000-fold more cytotoxic than the parent drug. The pharmacokinetics of irinotecan are extremely complex and have been the subject of intensive investigation in recent years. Irinotecan is subject to extensive metabolism by various polymorphic enzymes, including CES2 to form SN-38, members of the UGT1A subfamily, and CYP3A4 and CYP3A5, which form several pharmacologically inactive oxidation products. Elimination of irinotecan is also dependent on drug-transporting proteins, notably ABCB1 (P-glycoprotein), ABCC2 (cMOAT) and ABCG2 (BCRP), present on the bile canalicular membrane. The various processes mediating drug elimination, either through metabolic breakdown or excretion, likely impact substantially on interindividual variability in drug handling. This report provides an update on current strategies to individualize irinotecan chemotherapy based on each patient's genetic constitution, which may ultimately lead to more selective use of this agent.

DrugBank Data that Cites this Article

Drug Enzymes

Drug	Enzyme	Kind	Organism	Pharmacological Action	Actions
Irinotecan	Cytochrome P450 3A4	Protein	Humans	Unknown	Substrate Inhibitor	Details
Irinotecan	Cytochrome P450 3A5	Protein	Humans	Unknown	Substrate	Details
Irinotecan	UDP-glucuronosyltransferase 1-1	Protein	Humans	Unknown	Substrate	Details
Irinotecan	UDP-glucuronosyltransferase 1-9	Protein	Humans	Unknown	Substrate	Details

Drug Transporters

Drug	Transporter	Kind	Organism	Pharmacological Action	Actions
Irinotecan	ATP-binding cassette sub-family G member 2	Protein	Humans	Unknown	Substrate	Details
Irinotecan	Canalicular multispecific organic anion transporter 1	Protein	Humans	Unknown	Substrate	Details
Irinotecan	P-glycoprotein 1	Protein	Humans	Unknown	Substrate	Details

Drug Interactions

• Approved
• Vet approved
• Nutraceutical
• Illicit
• Withdrawn
• Investigational
• Experimental
• All Drugs

Drugs	Interaction
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Irinotecan Methimazole	The serum concentration of the active metabolites of Irinotecan can be decreased when Irinotecan is used in combination with Methimazole.
Irinotecan Ritonavir	The serum concentration of the active metabolites of Irinotecan can be decreased when Irinotecan is used in combination with Ritonavir.
Irinotecan Ketoconazole	The serum concentration of the active metabolites of Irinotecan can be decreased when Irinotecan is used in combination with Ketoconazole.
Irinotecan Nefazodone	The serum concentration of the active metabolites of Irinotecan can be decreased when Irinotecan is used in combination with Nefazodone.
Irinotecan Itraconazole	The serum concentration of the active metabolites of Irinotecan can be decreased when Irinotecan is used in combination with Itraconazole.