Also, UGT1A1 conjugates bilirubin and bilirubin glucuronidation is another risk factor for increased toxicity

De-conjugation by β-glucuronidases
The intestinal bacteria produced β-glucuronidases that de-conjugate SN-38G to SN-38 resulting in entero-hepatic re-circulation of SN-38. Metabolism by cytochrome P450 enzymes
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. Induction or inhibition of CYP3A enzymes by smoking, some herbs and medications may result in interactions with irinotecan. Transport to bile
Irinotecan is transported to bile by the ATP-binding cassette (ABC) transporter proteins: ABCB1, ABCC1, ABCC2, and ABCG2. Elimination
Irinotecan clearance is mainly biliary (66%) and estimated 12–21 L/h/m2. All metabolites, except SN-38G, are mainly excreted in feces. Irinotecan  elimination half-lives were reported between 5 to18 h. SN-38 half-lives were reported between  6 and 32 h.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. 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 have Gilberts 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.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 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. Irinotecan is one of the first widely used chemotherapy agents that is dosed according to the recipients genotype. Approval
Irinotecan received accelerated approval from the U.S. Food and Drug Administration (FDA) in 1996, and full approval in 1998. Names
During development, it was known as CPT-11. Formulations
A liposome encapsulated version of irinotecan sold as Onivyde by Merrimack Pharmaceuticals, was approved by FDA in October 2015, to treat metastatic pancreatic cancer. It was approved for medical use in the European Union in October 2016. See also
Etirinotecan pegol, an experimental derivative of irinotecan with a longer half-life in the human body

References
Further reading
Dean L (2015). "Irinotecan Therapy and UGT1A1 Genotype". In Pratt VM, McLeod HL, Rubinstein WS,  et al. (eds.). Medical Genetics Summaries. National Center for Biotechnology Information (NCBI). PMID 28520360. Bookshelf ID: NBK294473. External links
"Irinotecan". Drug Information Portal. U.S. National Library of Medicine. "Irinotecan hydrochloride". Drug Information Portal. U.S. National Library of Medicine. Irinotecan Pathway on PharmGKB