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UGTIO
60349
Sequencing, Irinotecan Hypersensitivity
Clinical Information: Following primary metabolism by the phase I enzymes (by oxidation,
reduction, dealkylation, and cleavage in the intestines and liver), many drugs and their metabolites are
further modified for excretion by a group of conjugative, phase II enzymes. One of these phase II
enzymes, uridine diphosphate (UDP)-glycuronosyl transferase 1A1 (UGT1A1), is responsible for
bilirubin conjugation with glucuronic acid. This renders the bilirubin water soluble and permits
excretion of the bilirubin-glucuronide conjugates in urine.(1) UGT1A1 is involved in the metabolism of
irinotecan, a topoisomerase I inhibitor. Irinotecan is a chemotherapy drug used to treat solid tumors
including colon, rectal, and lung cancers. It is a prodrug that forms an active metabolite, SN-38. SN-38
is normally inactivated by conjugation with glucuronic acid followed by biliary excretion into the
gastrointestinal tract. If UGT1A1 activity is impaired or deficient due to mutations in the coding region
or promoter TA (thymine, adenine) repeat polymorphisms, SN-38 fails to become conjugated with
glucuronic acid, increasing the concentration of SN-38. This can result in severe neutropenia. The
combination of neutropenia with diarrhea can be life-threatening.(3,4) The UGT1A1 gene maps to
chromosome 2q37 and contains 5 exons. The promoter, exons, exon-intron boundaries, and a region in
the distal promoter called the "phenobarbital response enhancer module," which is associated with
transcriptional activity of the gene, are assessed for polymorphisms and mutations in this assay.(5) More
than 100 mutations have been described in the UGT1A1 gene; 42 of the described mutations have
decreased enzyme activity.
Useful For: Identifying individuals who are at increased risk of adverse drug reactions with
irinotecan and who should be considered for decreased dosing of the drug
Interpretation: An interpretive report will be provided.
Reference Values:
An interpretive report will be provided.
Clinical References: 1. Guilemette C: Pharmacogenomics of human
UDP-glucuronosyl-transferase enzymes. Pharmacogenomics J 2003;3:136-158 2. Innocenti F, Grimsley
C, Das S, et al: Haplotype structure of the UDP-glucuronosyltransferase 1A1 promoter in different
ethnic groups. Pharmacogenetics 2002;12:725-733 3. Goetz MP, Safgren S, Goldberg RM, et al: A
phase I dose escalation study of irinotecan (CPT-11), oxaliplatin (Oxal), and capecitabine (Cap) within
three UGT1A1 TA promoter cohorts (6/6, 6/7, and 7/7). ASCO 2005 ASCO Annual Meeting Abstract
No: 2014 4. NDA 20-571/S-024/S-027/S-028. Camptosar (Irinotecan HCL) Final Label. July 21, 2005.
Pfizer 5. Kitagawa C, Ando M, Ando Y, et al: Genetic polymorphism in the Phenobarbital-responsive
enhancer module of the UDP-glucuronosyltransferase 1A1 gene and irinotecan toxicity. Pharmacogenet
Genomics 2005;15:35-41
UDP-Glucuronosyl Transferase 1A1 (UGT1A1), Full Gene
Sequencing, Irinotecan Hypersensitivity, Saliva
Clinical Information: Following primary metabolism by the phase I enzymes (by oxidation,
reduction, dealkylation, and cleavage in the intestines and liver), many drugs and their metabolites are
further modified for excretion by a group of conjugative, phase II enzymes. One of these phase II
enzymes, uridine diphosphate (UDP)-glycuronosyl transferase 1A1 (UGT1A1), is responsible for
bilirubin conjugation with glucuronic acid. This renders the bilirubin water soluble and permits
excretion of the bilirubin-glucuronide conjugates in urine.(1) UGT1A1 is involved in the metabolism of
irinotecan, a topoisomerase I inhibitor. Irinotecan is a chemotherapy drug used to treat solid tumors
including colon, rectal, and lung cancers. It is a prodrug that forms an active metabolite, SN-38. SN-38
is normally inactivated by conjugation with glucuronic acid followed by biliary excretion into the
gastrointestinal tract. If UGT1A1 activity is impaired or deficient due to mutations in the coding region
or promoter TA (thymine, adenine) repeat polymorphisms, SN-38 fails to become conjugated with
glucuronic acid, increasing the concentration of SN-38. This can result in severe neutropenia. The
combination of neutropenia with diarrhea can be life-threatening.(3,4) The UGT1A1 gene maps to
chromosome 2q37 and contains 5 exons. The promoter, exons, exon-intron boundaries, and a region in
the distal promoter called the "phenobarbital response enhancer module," which is associated with
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