Xiang Xiaoqiang, Jada Srinivasa Rao, Li Hui Hua, Fan Lu, Tham Lai San, Wong Chiung Ing, Lee Soo Chin, Lim Robert, Zhou Qing Yu, Goh Boon Cher, Tan Eng Huat, Chowbay Balram
Laboratory of Clinical Pharmacology, Division of Medical Sciences, National Cancer Centre, National University Hospital, Singapore.
Pharmacogenet Genomics. 2006 Sep;16(9):683-91. doi: 10.1097/01.fpc.0000230420.05221.71.
To investigate the pharmacogenetic effect of SLCO1B1 *1a, *1b, *5 and *15 polymorphisms on irinotecan disposition in Asian cancer patients.
Irinotecan was administered over 90 min either at 100 mg/m on days 1, 8 and 15 with the regimen being repeated every 28 days (N=28) or at 375 mg/m once every three weeks (N=43). Plasma concentrations of irinotecan, 7-ethyl-10-hydroxycamptothecin and 7-ethyl-10-hydroxycamptothecinG were analysed after the first dose of the first cycle and the influence of SLCO1B1 *1a, *1b, *5 and *15 polymorphisms on the disposition of irinotecan and its metabolites were evaluated.
Pharmacokinetic parameters were obtained from 71 cancer patients. Genotypic-phenotypic correlates showed the clearance of irinotecan to be 3-fold lower in patients carrying the *15 haplotype than cancer patients with the reference genotype *1a/*1a (9.57+/-3.15 vs. 28.86+/-10.97 l/h/m; P=0.001). The area under the plasma concentration-time curve from zero to infinity and normalized by dose and body surface area (AUC0-nf/dose/BSA) were significantly higher in patients harbouring the *15 haplotype than patients with the reference genotype for irinotecan (39.27+/-15.17 vs. 17.32+/-6.30 h/m; P=0.003) and 7-ethyl-10-hydroxycamptothecin (1.28+/-0.53 vs. 0.69+/-0.32 h/m; P=0.021). The exposure levels to 7-ethyl-10-hydroxycamptothecinG also showed a statistically significant trend among the SLCO1B1 haplotype pairs, being approximately 10-fold lower in patients with *15 haplotype than with patients harbouring the reference genotype (3.57+/-1.95 vs. 12.0+/-6.09 h/m; P=0.016).
These findings suggest that (1) SLCO1B1 haplotypes may have a significant influence on the disposition of irinotecan and its metabolites in Asian cancer patients, and (2) patients with SLCO1B1*15 haplotype may be susceptible to increased sensitivity to irinotecan, which may manifest itself either by increased efficacy or toxicity or both owing to the increased exposure levels to 7-ethyl-10-hydroxycamptothecin.
研究SLCO1B1 *1a、*1b、5和15基因多态性对亚洲癌症患者伊立替康处置的药物遗传学效应。
伊立替康在第1、8和15天以100 mg/m²的剂量在90分钟内给药，每28天重复一次该方案（N = 28），或者每三周以375 mg/m²的剂量给药一次（N = 43）。在第一个周期的第一剂给药后分析伊立替康、7-乙基-10-羟基喜树碱和7-乙基-10-羟基喜树碱G的血浆浓度，并评估SLCO1B1 *1a、*1b、5和15基因多态性对伊立替康及其代谢产物处置的影响。
从71例癌症患者中获得了药代动力学参数。基因型-表型相关性显示，携带15单倍型的患者中伊立替康的清除率比具有参考基因型1a/1a的癌症患者低3倍（9.57±3.15对28.86±10.97 l/h/m²；P = 0.001）。对于伊立替康，携带15单倍型的患者从零到无穷大的血浆浓度-时间曲线下面积经剂量和体表面积归一化后（AUC0-nf/剂量/BSA）显著高于具有参考基因型的患者（39.27±15.17对17.32±6.30 h/m²；P = 0.003），对于7-乙基-10-羟基喜树碱也是如此（1.28±0.53对0.69±0.32 h/m²；P = 0.021）。在SLCO1B1单倍型对中，7-乙基-10-羟基喜树碱G的暴露水平也显示出统计学上的显著趋势，携带*15单倍型的患者比携带参考基因型的患者低约10倍（3.57±1.95对12.0±6.09 h/m²；P = 0.016）。
这些发现表明：（1）SLCO1B1单倍型可能对亚洲癌症患者中伊立替康及其代谢产物的处置有显著影响；（2）携带SLCO1B1*15单倍型的患者可能对伊立替康敏感性增加，这可能由于7-乙基-10-羟基喜树碱暴露水平增加而表现为疗效增加、毒性增加或两者兼有。
