title: Role of UGT1A1*6, UGT1A1*28 and ABCG2 c.421C>A polymorphisms in irinotecan-induced neutropenia in Asian cancer patients.
abstract: The objectives of the present study were (i) to study the pharmacogenetics of UGT1A1*6, UGT1A1*28 and ABCG2 c.421C>A in three distinct healthy Asian populations (Chinese, Malays and Indians), and (ii) to investigate the polygenic influence of these polymorphic variants in irinotecan-induced neutropenia in Asian cancer patients. Pharmacokinetic and pharmacogenetic analyses were done after administration of irinotecan as a 90-min intravenous infusion of 375 mg/m(2) once every 3 weeks (n = 45). Genotypic-phenotypic correlates showed a non-significant influence of UGT1A1*28 and ABCG2 c.421C>A polymorphisms on the pharmacokinetics of SN-38 (P > 0.05), as well as severity of neutropenia (P > 0.05). Significantly higher exposure levels to SN-38 (P = 0.018), lower relative extent of glucuronidation (REG; P = 0.006) and higher biliary index (BI; P = 0.003) were found in cancer patients homozygous for the UGT1A1*6 allele compared with patients harboring the reference genotype. The mean absolute neutrophil count (ANC) was 85% lower and the prevalence of grade 4 neutropenia (ANC < or = 500/microL) was 27% in patients homozygous for UGT1A1*6 compared with the reference group. Furthermore, the presence of the UGT1A1*6 allele was associated with an approximately 3-fold increased risk of developing severe grade 4 neutropenia compared with patients harboring the reference genotype. These exploratory findings suggest that homozygosity for UGT1A1*6 allele may be associated with altered SN-38 disposition and may increase the risk of severe neutropenia in Asian cancer patients, particularly in the Chinese cancer patients who comprised 80% (n = 36) of the patient population in the present study.
authors.affiliation: Laboratory of Clinical Pharmacology, Division of Medical Sciences, Humphrey Oei Institute of Cancer Research, National Cancer Center, 11 Hospital Drive, Singapore 169610.
authors.forename: Srinivasa Rao
authors.initials: SR
authors.lastname: Jada
authors.forename: Robert
authors.initials: R
authors.lastname: Lim
authors.forename: Chiung Ing
authors.initials: CI
authors.lastname: Wong
authors.forename: Xiaochen
authors.initials: X
authors.lastname: Shu
authors.forename: Soo Chin
authors.initials: SC
authors.lastname: Lee
authors.forename: Qingyu
authors.initials: Q
authors.lastname: Zhou
authors.forename: Boon Cher
authors.initials: BC
authors.lastname: Goh
authors.forename: Balram
authors.initials: B
authors.lastname: Chowbay
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics* / Q000502:physiology; D000328:Adult; D000368:Aged; D000483:Alleles; D002166:Camptothecin / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D014453:Glucuronosyltransferase / Q000235:genetics* / Q000502:physiology; D006801:Humans; D007194:India / Q000453:epidemiology; D000077146:Irinotecan; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics; D008296:Malaysia / Q000453:epidemiology; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics* / Q000502:physiology; D009503:Neutropenia / Q000139:chemically induced* / Q000453:epidemiology / Q000235:genetics*; D011110:Polymorphism, Genetic; D012846:Singapore / Q000453:epidemiology; D014565:Urogenital Neoplasms / Q000188:drug therapy / Q000235:genetics; D000099148:UGT1A1 Enzyme
chemical_list: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D002166:Camptothecin; D014453:Glucuronosyltransferase; D000077146:Irinotecan; D009363:Neoplasm Proteins; D000099148:UGT1A1 Enzyme; C116614:ABCG2 protein, human