Development of clinical genome information systems for pharmacokinetics analysis

我们开发了一个临床基因组信息网格搜索系统，可以从两个或多个生命科学数据库（DB）中提取全面的药物相关信息，使用OGSA-WebDB技术，这是一种数据库网格技术。检索DB是TOXINET（药物不良反应文献信息DB）、PharmGKB（药物相关基因DB）、P2P蛋白（蛋白质信息DB）、LSBM（基因表达器官DB）、KEGG（途径信息DB）和JSNP（单核苷酸多态性（SNP）信息DB）。该系统可以提取与抗癌或其他药物不良反应相关的最新药物责任基因和器官、代谢途径数据以及蛋白质信息的参考，研究人员可以估计药物责任基因与药物不良反应之间的因果关系。利用此，我们验证了盐酸伊立替康和顺铂在联合治疗中的药物不良反应。其中，ABC转运蛋白参与细胞色素P450对外源物质的代谢，淀粉和蔗糖的代谢是其共同的代谢途径，共提取到56个SNP位点。根据临床病例数据创建了盐酸伊立替康的药代动力学分析算法。我们开发了一个临床基因组药代动力学模拟系统，在该系统中，在选择基因型（野生型、杂合子、纯合子）、身高、体重和实际药物剂量后，每个隔室中CPT-11、SN-38和SN-38 G的时间浓度变化可以可视化为图表。它还可以模拟^*28和^*6的UGT 1A 1等位基因类型模式。我们提出了一个临床基因组信息管理系统，包括临床基因组数据，病人的情况下，数据和药代动力学数据的系统规范。原型系统是在UNIX服务器上使用Apache2.2.0、PHP5.1.1、MySQL5.0.18和Java编程语言开发的。

We developed a clinical genome information grid search system that can extract comprehensive drug-related information from two or more life-science databases (DBs) using OGSA-WebDB technology, which is a database grid technology. The retrieval DBs are TOXINET (an adverse-drug-reaction document information DB), PharmGKB (a drug-related gene DB), Entrez Protein (a protein information DB), LSBM (a gene-expression organ DB), KEGG (a pathway-information DB), and JSNP (a single nucleotide polymorphism (SNP) information DB). The system can extract references to the newest drug responsibility genes and organs, metabolic pathway data, and protein information relevant to adverse reactions to anti-cancer or other drugs, and researchers can estimate the causal relationships between a drug responsibility gene and an adverse drug reaction. Using this, we verified the adverse drug reaction between irinotecan hydrochloride and cisplatin in combination therapy. The common pathways are the ABC transporters that are involved in the metabolism of xenobiotics by cytochrome P450, and starch and sucrose metabolism and 56 SNPs were extracted as relevant polymorphisms. A pharmacokinetics analysis algorithm for irinotecan hydrochloride was created based on clinical case data. We developed a clinical genome pharmacokinetics simulation system in which the chronological concentration change of CPT-11, SN-38, and SN-38G in each compartment can be visualized as a graph after selecting the genotype (wild-type, heterozygote, homozygote), body height, weight, and actual drug dose. It can also simulate the UGT1A1 allele type patterns of ^*28 and ^*6. We propose the system specifications for a clinical genome information-management system that includes clinical genome data, patient case data, and pharmacokinetics data. The prototype system was developed using Apache2.2.0, PHP5.1.1, MySQL5.0.18, and Java programming language on a UNIX server.