UGT1A1 - Camptosar (irinotecan) Metabolism
UGT1A1 is a member of the UDP-glucuronyltransferase superfamily of
enzymes that catalyze the glucuronidation of various compounds, including
endogenous compounds such as steroid homones and bilirubin, as well as
xenobiotics including Camptosar (irinotecan, CPT-11), an antineoplastic
agent of the topoisomerase I inhibitor class. Several recent publications
have reported an association between the UGT1A1 (TA)7/(TA)7 genotype and
toxicity to irinotecan.
Irinotecan, also known as CPT-11 and Camptosar, was approved in the U.S.
for the treatment of metastatic colorectal cancer after failure of first-line
treatment with 5-FU. The survival advantages associated with irinotecan.was
the basis for full FDA approval for irinotecan as a second-line therapy for
patients with metastatic colorectal cancer in September of 1998. Irinotecan
is also under evaluation in a broad spectrum of solid tumors.
In the promotor region of the UGT1A1*28 there is an insertion of a TA in the
TATAA element that decreases the glucuronidation of irinotecan. The
resultant genotype is either A(TA)5TAA, A(TA)6TAA, A(TA)7TAA or
A(TA)8TAA. The TA insertion is most common in Caucasian and African
populations. Frequencies for wild-type 6/6, heterozygous 6/7 and homozygous
7/7 are 41, 47 and 9%, respectively. Approximately 9% of the North
American population is homozygous for the UGT1A1*28 allele which has 7
TA repeats and these
patients are at increased risk of experiencing neutropenia when treated with
Camptosar (r).
(TA)6/(TA)6 is the normal genotype: Generally no change in the
administered dose of Camptosar provided that no other agents known to
interact with Camptosar are also administered.
(TA)6/(TA)7 Heterozygous: These patients have intermediate
UGT1A1activity and may be at increased risk for neutropenia; however,
clinical results have been variable and such patients have been shown to
tolerate normal starting doses.
(TA)7/(TA)7 Homozygous: Patients with this genotype should have their
starting dose reduced by at least one level of Camptosar. However, the
precise dose reduction is not known and subsequent dose modifications
should be considered based on individual patient's tolerance to treatment.
Full prescribing information, including clinical trial information,
safety, dosing, drug-drug interactions and contraindications is
available at: http://www.fda.gov/ohrms/dockets/ac/04/briefing/2004-4079B1_07_Pfizer-UGT1A1.pdf
For more information go to National Center for Biotechnology Information (NCBI).
Most abstracts and many full length pdf articles can be printed from this
web site.
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