Genetic linkage of UGT1A7 and UGT1A9 polymorphisms to UGT1A1*6 is associated with reduced activity for SN-38 in Japanese patients with cancer.
OBJECTIVE
The phenotypic effects of UGT1A7 and UGT1A9 genetic polymorphisms on the in vivo pharmacokinetics of irinotecan were examined.


METHODS
Eighty-four Japanese patients with cancer who received irinotecan-based chemotherapy were enrolled. Polymorphisms present in UGT1A7 (T to G transversion at -57 and UGT1A7*2 to *9), UGT1A9 (9 or 10 repeat of T at -118 [-118(T)9 or 10] and UGT1A9*2 to *5), and UGT1A1 (UGT1A1*6, UGT1A1*27, and UGT1A1*28) were analyzed for all patients. Pharmacokinetics of irinotecan were examined in 52 patients.


RESULTS
The most frequent haplotype (haplotype I, 56.7%, 95% CI 53.1-60.4) consisted of polymorphisms related to normal catalytic or transcriptional activity [T at -57 and *1 of UGT1A7, -118(T)10 of UGT1A9, and UGT1A1*1]. The second most frequent haplotype (haplotype II, 15.0%, 95% CI 12.4-18.3) consisted of polymorphisms related to reduced catalytic or transcriptional activity [-57T > G and *3 of UGT1A7 and -118(T)9 of UGT1A9 linked to UGT1A1*6]. The AUC(SN-38)/AUC(SN-38G) ratios in three patients homozygous for haplotype II were significantly higher than those in 20 patients with I/I diplotype (P = 0.011). Neither of these patients had UGT1A1*28.


CONCLUSIONS
Genetic linkage of UGT1A7 and UGT1A9 polymorphisms to UGT1A1*6, related to reduced catalytic and transcriptional activities of UGTs, is associated with the decreased glucuronosyltransferase activity for SN-38 in Japanese patients with cancer.
Fujita
Ken-ichi
K
Department of Clinical Oncology, Saitama Medical University, 38 Morohongou, Iruma-gun, Saitama 350-0495, Japan.
Ando
Yuichi
Y
Nagashima
Fumio
F
Yamamoto
Wataru
W
Eodo
Hisashi
H
Araki
Kazuhiro
K
Kodama
Keiji
K
Miya
Toshimichi
T
Narabayashi
Masaru
M
Sasaki
Yasutsuna
Y
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D044466:Asian People; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D005260:Female; D014453:Glucuronosyltransferase / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D000077146:Irinotecan; D007564:Japan; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000235:genetics*; D011110:Polymorphism, Genetic; D000090264:UDP-Glucuronosyltransferase 1A9
C000715591:UGT1A9 protein, human; D000077146:Irinotecan; D014453:Glucuronosyltransferase; D000090264:UDP-Glucuronosyltransferase 1A9; C107611:UDP-glucuronosyltransferase, UGT1A7; D002166:Camptothecin