Preclinical discovery of candidate genes to guide pharmacogenetics during phase I development: the example of the novel anticancer agent ABT-751.
Preclinical discovery of candidate genes to guide pharmacogenetics during phase I development: the example of the novel anticancer agent ABT-751.
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在 I 期开发过程中指导药物遗传学的候选基因的临床前发现：新型抗癌剂 ABT-751 的例子。
DOI：
10.1097/fpc.0b013e3283623e81
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发表时间：
2013
影响因子：
2.6
通讯作者：
Rata
中科院分区：
文献类型：
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作者：
Innocenti,Federico;Ramírez,Jacqueline;Obel,Jennifer;Xiong,Julia;Mirkov,Snezana;Chiu,Yi-Lin;Katz,DavidA;Carr,RobertA;Zhang,Wei;Das,Soma;Adjei,Araba;Moyer,AnnM;Chen,PeiXian;Krivoshik,Andrew;Medina,Diane;Gordon,GaryB;Rata
ABT-751是一种新型口服抗微管蛋白药物，主要以无活性的葡萄糖醛酸苷（ABT-751 G）和硫酸盐（ABT-751 S）结合物形式消除。我们进行了药物遗传学研究ABT-751的药代动力学，使用体外数据，以指导选择基因分型的ABT-751.MethodsUDP-葡萄糖醛酸基转移酶（UGT）和磺基转移酶（SULT）酶在体外ABT-751代谢产物的形成进行了筛选。结果UGT 1A 1、UGT 1A 4、UGT 1A 8、UGT 2B 7和SULT 1A 1参与了ABT-751葡萄糖醛酸苷（ABT-751 G）和硫酸盐（ABT-751 S）的形成。SULT 1A 1拷贝数（> 2）与ABT-751清除率平均增加34%（P= 0.044）、ABT-751 AUC降低18%（P= 0.045）和硫酸化代谢率增加50%（P= 0.025）相关。UGT 1A 8 rs6431558与葡萄糖醛酸化代谢率增加28%相关（P= 0.022），UGT 1A 4 * 2与ABT-751 C谷值降低65%相关（P= 0.009）。体外代谢筛选指导的候选基因的先验选择增强了我们识别患者间药代动力学变异性的遗传决定因素的能力。
ObjectiveABT-751, a novel orally available antitubulin agent, is mainly eliminated as inactive glucuronide (ABT-751G) and sulfate (ABT-751S) conjugates. We performed a pharmacogenetic investigation of ABT-751 pharmacokinetics using in-vitro data to guide the selection of genes for genotyping in a phase I trial of ABT-751.MethodsUDP-glucuronosyltransferase (UGT) and sulfotransferase (SULT) enzymes were screened for ABT-751 metabolite formation in vitro. Forty-seven cancer patients treated with ABT-751 were genotyped for 21 variants in these genes.ResultsUGT1A1, UGT1A4, UGT1A8, UGT2B7, and SULT1A1 were found to be involved in the formation of inactive ABT-751 glucuronide (ABT-751G) and sulfate (ABT-751S). SULT1A1 copy number (> 2) was associated with an average 34% increase in ABT-751 clearance (P= 0.044), an 18% reduction in ABT-751 AUC (P= 0.045), and a 50% increase in sulfation metabolic ratios (P= 0.025). UGT1A8 rs6431558 was associated with a 28% increase in glucuronidation metabolic ratios (P= 0.022), and UGT1A4* 2 was associated with a 65% decrease in ABT-751 C trough (P= 0.009).ConclusionThese results might represent the first example of a clinical pharmacokinetic effect of the SULT1A1 copy number variant on the clearance of a SULT1A1 substrate. A-priori selection of candidate genes guided by in-vitro metabolic screening enhanced our ability to identify genetic determinants of interpatient pharmacokinetic variability.