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Newsletter>
Irinotecan pathway genotype analysis
April 20, 2005
Irinotecan pathway genotype analysis to predict
pharmacokinetics.
PURPOSE: The purpose was to explore the relationships
between irinotecan disposition and allelic variants of
genes coding for adenosine triphosphate binding cassette
transporters and enzymes of putative relevance for
irinotecan. EXPERIMENTAL DESIGN: Irinotecan was
administered to 65 cancer patients as a 90-min infusion
(dose, 200-350 mg/m(2)), and pharmacokinetic data were
obtained during the first cycle. All patients were
genotyped for variants in genes encoding MDR1
P-glycoprotein (ABCB1), multidrug resistance-associated
proteins MRP-1 (ABCC1) and MRP-2 (canalicular multispecific
organic anion transporter; ABCC2), breast cancer resistance
protein (ABCG2), carboxylesterases (CES1, CES2), cytochrome
p450 isozymes (CYP3A4, CYP3A5), UDP glucuronosyltransferase
(UGT1A1), and a DNA-repair enzyme (XRCC1), which was
included as a nonmechanistic control. RESULTS: Eighteen
genetic variants were found in nine genes of putative
importance for irinotecan disposition. The homozygous T
allele of the ABCB1 1236C>T polymorphism was associated
with significantly increased exposure to irinotecan (P =
0.038) and its active metabolite SN-38 (P = 0.031).
Pharmacokinetic parameters were not related to any of the
other multiple variant genotypes, possibly because of the
low allele frequency. The extent of SN-38 glucuronidation
was slightly impaired in homozygous variants of UGT1A1*28,
although differences were not statistically significant (P
= 0.22). CONCLUSIONS: It is concluded that genotyping for
ABCB1 1236C>T may be one of the factors assisting with dose
optimization of irinotecan chemotherapy in cancer patients.
Additional investigation is required to confirm these
findings in a larger population and to assess relationships
between irinotecan disposition and the rare variant
genotypes, especially in other ethnic groups.
Ref: Mathijssen RH, Marsh S, Karlsson MO, Xie R, Baker SD,
Verweij J, Sparreboom A, McLeod HL.--- Clin Cancer Res.
2003 Aug 15;9(9):3246-53.
Department of Medical Oncology, Erasmus MC-Daniel den Hoed
Cancer Center, 3075 EA Rotterdam, the Netherlands.
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