标题：Association of ATP-Binding Cassette, Sub-family C, Number 2 (ABCC2) Genotype with Pharmacokinetics of Irinotecan in Japanese Patients with Metastatic Colorectal Cancer Treated with Irinotecan Plus Infusional 5-Fluorouracil/Leucovorin (FOLFIRI)
摘要：ATP-binding cassette, sub-family C, number 2 ( ABCC2 ) is involved in the biliary excretion of irinotecan and its metabolites, SN-38 and SN-38 glucuronide. Effects of the ABCC2 genotype on the pharmacokinetics (PK) of irinotecan and the metabolites were examined in Japanese patients with metastatic colorectal cancer receiving irinotecan plus infusional 5-fluorouracil/leucovorin (FOLFIRI). ABCC2 genotypes (−1549G>A, −1023G>A, −1019A>G, −24C>T, 1249G>A and 3972C>T) and haplotypes were analyzed for 67 patients with cancer. PK was also examined in a subset of 31 patients receiving FOLFIRI. Relationship between the ABCC2 genotypes or diplotypes and area under the time–concentration curve ( AUC ) of irinotecan and the metabolites normalized by irinotecan dose was analyzed. The lower AUC of irinotecan was seen in patients with A/A or G/A genotypes at 1249 of the ABCC2 gene than others ( p =0.011, Mann–Whitney U teat). AUC of SN-38 in patients with A/A or G/A genotypes at −1023 was significantly lower than that in others ( p =0.018). The haplotype I included −1023A (G A ACGC) was the most frequent one with the allele frequency of 0.366. The AUC of SN-38 observed in patients with diplotypes harboring at least one haplotype I was lower than that observed in others ( p =0.023). The haplotype IV consisted of 1249 (GGAC A C) and was the fourth most frequent one with the allele frequency of 0.127. Patients with diplotypes carrying at least one haplotype IV showed lower AUC of irinotecan than others ( p =0.011). Thus, ABCC2 genotype is one of the predictors of the variability of irinotecan PK in Japanese patients with metastatic colorectal cancer receiving FOLFIRI.
关键词：multidrug-resistance protein 2;biliary excretion;irinotecan;SN-38;systemic exposure
