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Unit Code 83949:
UDP-Glycuronosyl Transferase 1A1 TA Repeat Genotype, UGT1A1

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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  

 

Confirmation of a diagnosis of Gilbert syndrome

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. Partial deficiency of UGT1A1 manifests as

Gilbert syndrome, a mild familial unconjugated

hyperbilirubinemia that may present only under stress. More

severe deficiencies of UGT1A1 manifest as Crigler-Najjar

syndromes I and II with markedly greater degrees of

unconjugated hyperbilirubinemia.

 

UGT1A1 is also 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, 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.  

 

The most common cause of irinotecan-induced neutropenia

results from insertion of extra TA (thymine, adenine) repeats in

the TATA box of the UGT1A1 promoter. This results in

decreased expression of the UGT1A1 gene in individuals

homozygous for these promoter polymorphisms, and is found

frequently with Gilbert syndrome. The number of TA repeats

is inversely related to gene expression. Individuals with normal

levels of UGT1A1 expression have 6 copies of the TA repeat in

the promoter (referred to as the *1 allele) or more rarely 5 copies

of the TA repeat (referred to as *36). Individuals with decreased

expression of UGT1A1 have 7 TA repeats (*28 allele) or 8 TA

repeats (*37). Approximately 10% to 15% of Caucasians and

African Americans are homozygous for the TA7 repeat (*28/*28),

and these individuals have a 50% higher risk of experiencing

severe (grade 4 or 5) neutropenia following the administration of

irinotecan. Approximately 40% of individuals treated with

irinotecan are heterozygous for the TA7 repeat polymorphism

(ie, TA6/TA7 or *1/*28). These individuals are also at increased

risk of grade 4 neutropenia. Recently, the package labeling for

irinotecan has been changed to indicate that individuals

homozygous or heterozygous for polymorphisms present in the

TATA box of the UGT1A1 promoter have a higher risk for

severe or life-threatening neutropenia. It appears that the risk is

greatest for individuals who receive irinotecan once every 3

weeks.

Reference Values

An interpretive report will be provided.

Interpretation

An interpretive report will be provided.

 

Drug-drug interactions must be considered when predicting the

UGT1A1 phenotype, especially in individuals heterozygous for

the TA7 polymorphism (see "Cautions").

Cautions

This test does not detect polymorphisms other than *1, *28, *36,

and *37. Numerous polymorphisms and rare mutations have

been described that impair UGT1A1 activity.

 

Liver or renal dysfunction may result in adverse drug reactions

with irinotecan independently of TA-repeat polymorphisms.

 

Drugs that significantly inhibit cytochrome P450 3A4, such as

ketoconazole, increase patient exposure to irinotecan and its

active metabolite SN-38, potentially causing or increasing the

severity of an adverse drug reaction. The package labeling

should be consulted for additional information.

 

Drugs that induce the overexpression of cytochrome P450 3A4,

including anticonvulsant medications (such as phenytoin,

phenobarbital, and carbamazepine) and rifampin, will cause

substantial reduction in exposure to irinotecan and its active

metabolite SN-38. The package labeling should be consulted

for changes to the use of other medications.

 

Herbal supplements that induce the overexpression of

cytochrome P450 3A4 such as St. John's Wort, will cause

substantial reduction in exposure to irinotecan and its active

metabolite SN-38. The package labeling should be consulted

for changes to the use of other medications.

Special Instructions and Forms

• Informed Consent Form for DNA Testing 
• Multiple Drug Metabolism Genotype Tests 

Clinical Reference

1.   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

 

2.   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

 

3.   Package insert:  NDA 20-571/S-024/S-027/S-028. Camptosar

      (Irinotecan HCL) Final Label. Pfizer Inc, NY, rev 7/05

Key