Zhou Qingyu, Sparreboom Alex, Tan Eng-Huat, Cheung Yin-Bun, Lee Ann, Poon Donald, Lee Edmund J D, Chowbay Balram
Laboratory of Clinical Pharmacology, Division of Clinical Trials and Epidemiological Sciences, National Cancer Centre, Singapore 169610.
Br J Clin Pharmacol. 2005 Apr;59(4):415-24. doi: 10.1111/j.1365-2125.2004.02330.x.
The aim of this exploratory study was to investigate associations between irinotecan pharmacokinetic parameters and allelic variants in genes encoding for drug transporters and drug metabolizing enzymes that are involved in irinotecan disposition in Asian patients with cancer.
Irinotecan was administered at 100 mg m(-2) over 90 min on a weekly schedule to 29 nasopharyngeal carcinoma patients and pharmacokinetic analysis was performed during the first cycle. All patients were genotyped for allelic variants in genes encoding drug metabolizing enzymes (CYP3A4, CYP3A5, UGT1A1) and drug transporters (ABCB1, ABCC2 and ABCG2) that are involved in irinotecan disposition.
Of the six candidate genes that were analyzed, 11 genetic variants were found. Significant genotypic-phenotypic associations were apparent only for transporter genes. The C(max) of irinotecan was significantly lower in patients carrying the CC genotype at exon 26 of the ABCB1 gene compared with those harbouring at least one variant allele (P = 0.047). Patients harbouring the wild type ABCG2 CTCA genotype were associated with significantly higher values for relative extent of conversion (REC) of irinotecan to SN-38 compared with patients carrying at least one deletion CTCA allele (P = 0.019).
The present exploratory study shows that genetic polymorphisms in drug transporter genes, particularly in ABCB1 and ABCG2 genes, may be important in influencing the pharmacokinetics of irinotecan and its metabolites. The predictive value of the identified allelic variants in the ABCG2 and ABCB1 genes on irinotecan disposition should be further investigated in a larger patient population as well as in other ethnic populations.
本探索性研究旨在调查亚洲癌症患者中，伊立替康药代动力学参数与参与伊立替康处置的药物转运体和药物代谢酶编码基因的等位基因变异之间的关联。
29例鼻咽癌患者每周接受一次伊立替康治疗，剂量为100mg/m²，静脉滴注90分钟，在第一个周期内进行药代动力学分析。对所有患者进行基因分型，检测参与伊立替康处置的药物代谢酶（CYP3A4、CYP3A5、UGT1A1）和药物转运体（ABCB1、ABCC2和ABCG2）编码基因的等位基因变异。
在分析的6个候选基因中，发现了11个基因变异。仅在转运体基因中观察到显著的基因型-表型关联。携带ABCB1基因第26外显子CC基因型的患者，伊立替康的Cmax显著低于携带至少一个变异等位基因的患者（P = 0.047）。与携带至少一个CTCA缺失等位基因的患者相比，携带野生型ABCG2 CTCA基因型的患者，伊立替康向SN-38的相对转化程度（REC）显著更高（P = 0.019）。
本探索性研究表明，药物转运体基因的遗传多态性，特别是ABCB1和ABCG2基因的多态性，可能对伊立替康及其代谢产物的药代动力学有重要影响。ABCG2和ABCB1基因中已鉴定的等位基因变异对伊立替康处置的预测价值，应在更大规模的患者群体以及其他种族群体中进一步研究。
