Feng, Xiaodong_ Xie, Hong-Guang - Applying pharmacogenomics in therapeutics-CRC Press (2016)

Pharmacogenomics and Laboratory Medicine
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polymorphism is high among Japanese and Chinese (16–23%) but is very low in the
white population (<1%) (Ando et al. 2000). The high frequency of the UGT1A1*6
allele may contribute to the high incidence of neonatal hyperbilirubinemia in the
East Asian populations, consistent with a major role of UGT1A1 in the glucuronidation
of bilirubin. In addition, the UGT1A1*6 allele is associated with the development
of irinotecan-induced toxicities. Patients either heterozygous or homozygous
for the UGT1A1*6 allele are at a higher risk for developing neutropenia, diarrhea,
dose modification, and increased exposure to the cytotoxic SN-38 metabolite as
compared to those with the UGT1A1*1/*1 genotype.
The UGT1A1*28 allele (rs8175347) has a homozygous 2-bp insertion (TA) in the
TATA box promoter region of the UGT1A1 gene. The presence of an extra TA repeat
in the TATA box significantly decreases UGT1A1 transcription, resulting in reduced
enzymatic activity and glucuronidation (Innocenti et al. 2006). The UGT1A1*28
allele is found in many cases of Gilbert syndrome, but it is also associated with an
increased risk for neutropenia in patients receiving irinotecan. Compared to carriers
of the UGT1A1*1/*1 or *1/*28 genotype, patients with the *28/*28 genotype are
at an increased risk for developing neutropenia when treated with irinotecan. This
may be contradictory since some studies found no link between the *28 allele and
neutropenia. Patients homozygous for the UGT1A1*28 allele are also at an increased
risk for developing diarrhea after receiving irinotecan, but this is also contradictory
because results from individual studies have been mixed. A meta-analysis with
1760 patients across 20 studies found that the correlation between UGT1A1*28 allele
and developing diarrhea after irinotecan treatment depends on dosage. Compared
to the *1/*1 genotype, patients with either the *28/*28 or *1/*28 genotype are at
a significantly greater risk for experiencing severe diarrhea after taking medium
(150–250 mg/m²) or high doses (≥250 mg/m²) of irinotecan, with no associations
found in patients taking a low (<150 mg/m²) dose of irinotecan.
Similar to the UGT1A1*6 allele, the frequency of the UGT1A1*28 allele also varies
across ethnic groups. Approximately 10% of the US population is homozygous
for UGT1A1*28. The highest frequency is found in the African population (~43%),
followed by that in the white population (~39%), and in the Asian population (~16%).
Variants with 5 or 8 TA repeats occur primarily in individuals of African descent at
much lower frequencies (~3–7%) (Beutler et al. 1998).
In summary, pharmacogenetic knowledge of the UGT1A1 polymorphism status
could help reduce the risk of severe toxicity and improve the chance of maintaining
therapy by guiding the selection of the appropriate starting dosages. In fact,
the US FDA has recommended that patients with the *28/*28 genotype receive a
lower starting dose of irinotecan on the label of the drug since 2004. But the Dutch
Pharmacogenetics Working Group recommends reducing irinotecan dose by 30%
only when high dose (250 mg/m²) is used for patients with the *28/*28 genotype.
DRUG TRANSPORTERS
Drug transporters play important roles in modulating the disposition and excretion
of a large number of drugs. In many cases, drug transporters are also critical determinants
of extent of drug entry into their target organs. In addition to drug–drug