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)
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)
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DOI：
10.1248/bpb.31.2137
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发表时间：
2008-11-01
影响因子：
2
通讯作者：
Sasaki, Yasutsuna
中科院分区：
文献类型：
--
作者：
Fujita, Ken-ichi;Nagashima, Fumio;Sasaki, Yasutsuna
ATP结合盒，C亚家族，编号2(ABCC2)参与伊立替康及其代谢产物SN-38和SN-38葡萄糖醛酸苷的胆汁排泄。观察了日本转移性结直肠癌患者接受伊立替康联合5-氟尿嘧啶/亚叶酸钙(FOLFIRI)治疗后，ABCC2基因对伊立替康及其代谢产物药代动力学的影响。对67例癌症患者的ABCC2基因(-1549G>；A、-1023G>；A、-1019A>；G、-24C>；T、1249G>；A和3972C>；T)和单倍型进行了分析。接受FOLFIRI的31名患者也进行了PK检查。分析ABCC2基因型或二倍型以及伊立替康的时间-浓度曲线下面积(AUC)与伊立替康剂量归一化代谢物的关系。ABCC2基因第1249位A/A或G/A基因型患者伊立替康的AUC值明显低于其他患者(P=0.011，Mann-Whitney U teat)。在-1023A/A或G/A等位基因携带者中，SN-38等位基因频率显著低于其他等位基因携带者(P=0.018)。其中-1023A(GAACGC)单倍型频率最高，等位基因频率为0.366。在至少含有一种单倍型I的双倍型患者中观察到的SN-38的AUC值低于其他患者(P=0.023)。单倍型IV由1249(GGACAC)组成，等位基因频率为0.127，居第4位。携带至少一个单倍型IV的双倍型患者伊立替康的AUC值低于其他患者(P=0.011)。因此，在接受FOLFIRI治疗的日本转移性结直肠癌患者中，ABCC2基因是伊立替康PK变异的预测因子之一。
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 (GAACGC) 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 (GGACAC) 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.