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Irinotecan pharmacogenetics: an overview for the community oncologist
University of Michigan Comprehensive Cancer Center, Ann Arbor, MI
Irinotecan is an important chemotherapeutic agent used primarily for colorectal cancer. However, irinotecan use is influenced by unpredictable toxicity, which may be severe, including neutropenia and diarrhea. SN-38, the active metabolite of irinotecan, is glucuronidated by UGT1A1, the enzyme that also glucuronidates bilirubin. Pharmacogenetic study has determined that UGT1A1 polymorphisms result in altered glucuronidation. Patients homozygous for the (TA)7TAA allele (UGT1A1*28) have reduced glucuronidation of SN-38 and are at increased risk for subsequent toxicity, particularly neutropenia. An estimated 1 in 10 North Americans is homozygous for UGT1A1*28. The oncologist should consider decreasing the irinotecan dose for any patient known to be homozygous for the UGT1A1*28 allele, have the hereditary hyperbilirubinemia syndrome, or have an elevated bilirubin level. Potential cytochrome P450 3A4 and UGT1A1 drug interactions should also be considered when dosing irinotecan. Genetic testing for UGT1A1 is available to determine TA6 and TA7 allele status. However, the impact of this assay and its use in routine practice remains uncertain and requires further investigation.
| Commun Oncol 2008;5:99–103 | full text |  168 kb |