Irinotecan, toxicity

Similar to 5-FU, there is a polymorphism associated with irinotecan toxicity. UDP-glucuronosyltransferase (UGT1A1) is an enzyme responsible for the glucuronidation of SN-38 to inactive metabolites, and reduced or deficient levels of this enzyme correlate with irinotecan-induced diarrhea and neutropenia.39 Recently the FDA approved a blood test that detects variations in this gene. This test will assist health care providers in predicting which patients may develop severe toxicities from normal doses of irinotecan and can be ordered prior to patients receiving irinotecan. binotecan is administered as an IV bolus over 60 to 90 minutes in a variety dosing schedules. 

UDP-glucuronosyltransferase gene and irinotecan toxicity a pharmaco-genetic analysis, Cancer Res. 2000, 60, 6921-6926. 

In conclusion, the homozygous or heterozygous genotype for UGTIAI 28 may be a significant risk factor for severe irinotecan toxicity. The example of irinotecan demonstrates clearly how polymorphisms in an inactivating metabolic pathway may affect the adverse events and therapeutic outcome in cancer chemotherapy. 

Ando, Y., Saka, H., Ando, M., et al. (2000) Polymorphisms of UDP-glucuronosyltransferase gene and irinotecan toxicity a pharmacogenetic analysis. Cancer Res. 60, 6921-6926. 

Invader UGTIAI molecular assay for irinotecan toxicity. A genetic test for an increased risk of toxicity from the cancer chemotherapy drug irinotecan (Camptosar). Med Lett Drugs Ther. 48, 39-40. 

The dose-limiting toxicities in irinotecan therapy are severe diarrhea and leukopenia (10). An increased plasma level of SN-38 may be an important mechanism for severe irinotecan toxicities. Biliary SN-38 G excreted into the small intestine is cleaved by bacterial glucuronidases in the colon to regenerate SN-38 therefore, this process is also... 

Association of UGTIA Polymorphisms with Severe Irinotecan Toxicities Depencency on Ethnicity and. Combination Therapy... 

Kitagawa C, Ando M, Ando Y et al. Genetic polymorphism in the phenobarbital-responsive enhancer module of the UDP-glucuronosyltransferase lAl gene and irinotecan toxicity. Pharmacogenet Genomics 2005 15 35 1. 

Ando M, Ando Y, Sekido Y et al. Genetic polymorphisms of the UDP-glucuronosyltransferase 1A7 gene and irinotecan toxicity in Japanese Cancer Patients. Jpn J Cancer Res 2002 93 591-597. 

Tukey RH, Strassburg CP, Mackenzie PI. Pharmacogenomics of human UDP-glucuronosyltransferases and irinotecan toxicity. Mol Pharmacol 2002 62 446-450. 

The role of UGT1A1 28 polymorphism and irinotecan toxicity has been extensively investigated in Japan by Ando et al. (26) and in the United States by... 

Lankisch TO, Schulz C, Zwingers T, etal. Gilbert s syndrome and irinotecan toxicity combination with UDP-glucuronosyltransferase 1A7 variants increases risk. Cancer Epidemiol Biomarkers Prev 2008 17(3) 695 701. 

In contrast to UGTlA-related irinotecan toxicity, where low enzyme activity results in prolonged exposure to a toxic metabolite, another common chemotherapeutic agent, tamoxifen, has received recent attention for the role of specific enzymes in conversion of this prodrug to its active metabolites. The second part of this article discusses the elfects of CYP variants on tamoxifen therapy. 

Ramchandani RP, Wang Y, Booth BP, etal. The role of SN-38 exposure, UGT1A1 28 polymorphism, and baseline bilirubin level in predicting severe irinotecan toxicity. J Clin Pharmacol 2007 47(l) 78-86. 

SaiK, Saito Y, Sakamoto H, etal. Importance of UDP-glucuronosyltransferase 1A1( )6 for irinotecan toxicities in Japanese cancer patients. Cancer Lett 2008 261 (2) 165—71. 

Recently, polymorphisms in ABCC2 have been found to influence irinotecan disposition in patients. In a study of 64 patients, Innocenti et al. recently reported that the 3972TT genotype was associated with higher AUCs of irinotecan and SN-38 compared to patients with TC or CC genotypes [51]. Genetic variants of ABGC2 will therefore influence irinotecan toxicity and tumor response. 

UDP-glucuronosyltransferase lAl (UGTIAI) that has been involved in irinotecan toxicity [20, 22],... 

---