Irinotecan

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 atropine with the first loose bowel movement.[13][14]

The immune system is adversely impacted by irinotecan. This is reflected in – sometimes dramatically – lowered white blood cell counts in the blood, in particular the neutrophils. The patient may experience neutropenia (a clinically significant decrease of neutrophils in the blood).[13][14]

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

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|alt=Irinotecan Pathway edit]]

Irinotecan Pathway edit

1. The interactive pathway map can be edited at WikiPathways: "IrinotecanPathway_WP229".

Irinotecan can be administered by 30- or 90-minute intravenous infusions of either 125 mg/m² weekly for four of every six weeks or 350 mg/m² every three weeks.[17]

Irinotecan is a hydrophilic compound with a large volume of distribution (400 L/m²).[17][18] At physiological pH, irinotecan and its active metabolite ethyl-10-hydroxy-camptothecin (SN-38) are present in two pH-dependent equilibrium isoforms; the anti tumor active lactone ring which hydrolyzed to the carboxylate isoform.[18]

In plasma, the majority of irinotecan and SN-38 are bound to albumin, which stabilizes their lactone forms. In blood, irinotecan and SN-38 are bound to platelets and red blood cells.[18]

Irinotecan has a linear pharmacokinetic. Population pharmacokinetic models assumed a three-compartmental model for irinotecan and a two-compartmental model for SN-38.[18]

SN-38 has a short distribution half-life (approximately 8 min). It reached its peak plasma concentration within 2 h after infusion. Also SN-38 exhibit a second peak in the plasma concentration because of its enterohepatic re-circulation and its release from erythrocytes.[18]

About 2–5% of the pro-drug irinotecan is hydrolyzed into its active metabolite SN-38 in the liver by two carboxylesterase converting enzymes (CES1 and CES2) and in plasma by butyrylcholinesterase (hBChE).[18][19] CES2 has a 12.5-fold higher affinity for irinotecan than CES1. While, butyrylcholinesterase has a 6-fold higher activity for irinotecan than CES.[18] After conversion, SN-38 is actively transported to the liver by the organic anion transporting polypeptide (OATP) 1B1 transporter.[18][19]

SN-38 is inactivated by glucuronidation to SN-38G (β-glucuronide conjugate) by several uridine diphosphate glucuronosyltransferase enzymes (UGTs) in the liver (UGT1A1, UGT1A9) and extra-hepatic (UGT1A1, UGT1A7, UGT1A10) and excreted into the bile.[18][19] Several UGT polymorphisms affects irinotecan pharmacokinetics, for example, the decreased UGT1 activity, may lead to severe toxicity. Also, UGT1A1 conjugates bilirubin and bilirubin glucuronidation is another risk factor for increased toxicity[18]

The intestinal bacteria produced β-glucuronidases that de-conjugate SN-38G to SN-38 resulting in entero-hepatic re-circulation of SN-38.[18][19]

Irinotecan is metabolized by intrahepatic cytochrome P450 enzymes, CYP3A4 and CYP3A5 into inactive metabolites APC (7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino] carbonyloxycamptothecin) and NPC (7-ethyl-10-[4-amino-1-piperidino] carbonyloxycamptothecin). NPC can be further converted by CES1 and CES2 in the liver to SN-38.[18][19] Induction or inhibition of CYP3A enzymes by smoking, some herbs and medications may result in interactions with irinotecan.[18]

Irinotecan is transported to bile by the ATP-binding cassette (ABC) transporter proteins: ABCB1, ABCC1, ABCC2, and ABCG2.[18][19]

Irinotecan clearance is mainly biliary (66%) and estimated 12–21 L/h/m².[18] All metabolites, except SN-38G, are mainly excreted in feces.[18][19] Irinotecan elimination half-lives were reported between 5 to18 h. SN-38 half-lives were reported between 6 and 32 h.[18]

There is high (30%) interindividual variability in irinotecan pharmacokinetic parameters which can be altered by several factors including age, sex, dose, administration timing, hepatic function, enzyme activity or hematocrit levels.[18][19]

People with variants of the UGT1A1 called TA₇, also known as the "*28 variant", express fewer UGT1A1 enzymes in their liver and often have 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.[20]

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.[20]

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.[3] Irinotecan is one of the first widely used chemotherapy agents that is dosed according to the recipient's genotype.[21]

During development, it was known as CPT-11.