UGT1A1 Genotyping for Irinotecan
Irinotecan (Camptosar) is a chemotherapeutic drug which is primarily used to treat metastatic colorectal cancer. Irinotecan is slowly metabolized by carboxyesterases into a pharmacologically active metabolite, 7-ethyl-10-hydroxycamptothecin (SN-38), which is 1,000 times more potent than the parent drug. SN-38 is then conjugated by the enzyme UDP-glycuronosyl transferase 1A1 (UGT1A1) to form an inactive metabolite, SN-38 glucuronide, which is readily excreted in bile and urine.
Irinotecan has a narrow therapeutic window, which is the difference between a therapeutic and a toxic dose. Twenty to 30% of patients who are treated with irinotecan develop severe diarrhea, neutropenia or both, primarily due to toxic levels of SN-38. Elevated SN-38 is usually caused by a polymorphism in the UGT1A1 gene that produces an enzyme variant with decreased activity. The most common allele associated with decreased enzyme activity and irinotecan toxicity is UGTA1A*28. Approximately 10 to 15% of Caucasians and African Americans are homozygous for UGTA1A*28 and these Individuals have a 50% higher risk of developing severe neutropenia. Approximately 40% of patients treated with irinotecan are heterozygous for UGTA1A*28 and are also at increased risk of developing neutropenia.
Advanced knowledge an individual’s UGTA1A genotype provides physicians with the information needed to determine which patients might benefit from a reduced dose of irinotecan.
