Influence of UGT1A9 intronic I399C>T polymorphism on SN-38 glucuronidation in Asian cancer patients.
Genetic polymorphisms in hepatically expressed UGT1A1 and UGT1A9 contribute to the interindividual variability i-n irinotecan disposition and toxicity. We screened UGT1A1 (UGT1A1*60, g.-3140G>A, UGT1A1*28 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/m(2) 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 (TG6GT(10)T/GG6GT(9)C) diplotype had 2.4-fold lower systemic exposure to SN-38 glucuronide (SN-38G) compared with patients harbouring the H1/H5 (TG6GT(10)T/GG6GT(10)C) 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.
Sandanaraj
E
E
Department of Pharmacy, Laboratory of Clinical Pharmacology, Division of Medical Sciences, Humphrey Oei Institute of Cancer Research, National Cancer Centre, Singapore.
Jada
S R
SR
Shu
X
X
Lim
R
R
Lee
S C
SC
Zhou
Q
Q
Zhou
S
S
Goh
B C
BC
Chowbay
B
B
D000328:Adult; D000368:Aged; D044466:Asian People; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000378:metabolism / Q000627:therapeutic use; D005260:Female; D020719:Glucuronides / Q000378:metabolism*; D014453:Glucuronosyltransferase / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D007438:Introns; D000077146:Irinotecan; D008099:Liver / Q000201:enzymology; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D011110:Polymorphism, Genetic; D000090264:UDP-Glucuronosyltransferase 1A9; D000099148:UGT1A1 Enzyme
D002166:Camptothecin; D020719:Glucuronides; D014453:Glucuronosyltransferase; D000077146:Irinotecan; D000090264:UDP-Glucuronosyltransferase 1A9; D000099148:UGT1A1 Enzyme; C441475:7-ethyl-10-hydroxycamptothecin glucuronide; C000715591:UGT1A9 protein, human