Role of UGT1A1*6, UGT1A1*28 and ABCG2 c.421C>A polymorphisms in irinotecan-induced neutropenia in Asian cancer patients.

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/m² 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 ≤ 500/µL) 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. ( Cancer Sci 2007; 98: 1461–1467) [ABSTRACT FROM AUTHOR]