In silico and in vitro pharmacogenetic analysis in mice
In silico and in vitro pharmacogenetic analysis in mice
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DOI：
10.1073/pnas.0700724104
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发表时间：
2007-11-06
影响因子：
11.1
通讯作者：
Peltz, Gary
中科院分区：
文献类型：
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作者：
Guo, Yinglying;Lu, Peng;Peltz, Gary
将小鼠肝脏体外药物生物转化系统的实验效率与计算机遗传学分析相结合，产生了一个模型系统，该模型系统可以快速分析药物代谢中的个体间差异。通过使用两种临床上重要的药物睾酮和伊立替康来测试该模型系统，这两种药物的代谢先前已得到充分表征。测量了这些药物与从15个近交系小鼠品系制备的肝脏体外生物转化系统孵育后产生的代谢物。16 α-羟基睾酮生成速率和伊立替康葡萄糖醛酸化的菌株特异性差异分别与Cyp 2b 9和Ugt 1a基因座内的遗传变异模式相关。使用表达的重组酶实验证实了这些计算预测。影响小鼠伊立替康代谢的遗传变化反映了已知影响该药物药代动力学和不良反应发生率的人类遗传变化。
Combining the experimental efficiency of a murine hepatic in vitro drug biotransformation system with in silico genetic analysis produces a model system that can rapidly analyze interinclividual differences in drug metabolism. This model system was tested by using two clinically important drugs, testosterone and irinotecan, whose metabolism was previously well characterized. The metabolites produced after these drugs were incubated with hepatic in vitro biotransformation systems prepared from the 15 inbred mouse strains were measured. Strain-specific differences in the rate of 16 alpha-hydroxytestosterone generation and irinotecan glucuroniclation correlated with the pattern of genetic variation within Cyp2b9 and Ugt1a loci, respectively. These computational predictions were experimentally confirmed using expressed recombinant enzymes. The genetic changes affecting irinotecan metabolism in mice mirrored those in humans that are known to affect the pharmacokinetics and incidence of adverse responses to this medication.