Influence of UGT1A9 intronic I399C4T polymorphism on SN-38 glucuronidation in Asian cancer patients

Chowbay, Balram, Goh, B, Jada, S, Lee, S, Lim, R, Sandanaraj, E, Shu, X, Zhou, Q, & Zhou, Shufeng (2008) Influence of UGT1A9 intronic I399C4T polymorphism on SN-38 glucuronidation in Asian cancer patients. Pharmacogenomics Journal, 8(3), pp. 174-185.

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Abstract

Genetic polymorphisms in hepatically expressed UGT1A1 and UGT1A9 contribute to the interindividual variability i-n irinotecan disposition and toxicity. We screened UGT1A1 (UGT1A160, g.−3140G>A, UGT1A128 and UGT1A1*6) and UGT1A9 (g.−118(T)9>10 and I399C>T) genes for polymorphic variants in the promoter and coding regions, and the genotypic effect of UGT1A9 I399C>T polymorphism on irinotecan disposition in Asian cancer patients was investigated. Blood samples were collected from 45 patients after administration of irinotecan as a 90 min intravenous infusion of 375 mg/m2 once in every 3 weeks. Genotypic–phenotypic correlates showed that cancer patients heterozygous or homozygous for the I399C>T allele had approximately 2-fold lower systemic exposure to SN-38 (P<0.05) and a trend towards a higher relative extent of glucuronidation (REG) of SN-38 (P>0.05). UGT1A1–1A9 diplotype analysis showed that patients harbouring the H1/H2 (TG6GT10T/GG6GT9C) diplotype had 2.4-fold lower systemic exposure to SN-38 glucuronide (SN-38G) compared with patients harbouring the H1/H5 (TG6GT10T/GG6GT10C) diplotype (P=0.025). In conclusion, this in vivo study supports the in vitro findings of Girard et al. and suggests that the UGT1A9 I399C>T variant may be an important glucuronidating allele affecting the pharmacokinetics of SN-38 and SN-38G in Asian cancer patients receiving irinotecan chemotherapy.

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ID Code: 30907
Item Type: Journal Article
Refereed: Yes
Keywords: UGT1A9, Polymorphism, Irinotecan, SN-38, Asians
DOI: 10.1038/sj.tpj.6500473
ISSN: 1470-269X
Divisions: Current > QUT Faculties and Divisions > Faculty of Health
Current > Institutes > Institute of Health and Biomedical Innovation
Deposited On: 12 Feb 2010 12:50
Last Modified: 18 Feb 2015 22:58

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