血药浓度监测与遗传多态性结合对OATP基因相关药物的个体化给药研究

OATP family is one of intake transporter and its substrates are also ranged in broad spectrum from endogenous exogenous compounds and xenobiotics. It plays an important role in drug absorption, distribution and eliminate. Methotrexate and digoxin, which are monitored in TDM, are substrates of OATP. The correlation of the concentration of the drugs and OATP gene polymorphisms is unknown, and the distribution of the genetic variation in the people administered the two drugs in China is unknown too. This information can provide the basis for individual differences in the course of medication. The preliminary work of our project team has established the method of OATP partial gene sequencing. Our aims are to obtain gene variant distribution characteristics in healthy population and the patients who use of these drugs. Second, on the basis of enough gene mutations cases, we want to carry out a comparative study of the pharmacokinetics on the patients to obtain the relationship between gene mutation and pharmacokinetics. Third，we hope to know the relationship of OATP polymorphisms and the concentrations.

OATP是摄入型转运体中的一大类，对内、外源性物质，尤其是药物的吸收、分布、消除具有重要影响。TDM常规监测的甲氨蝶呤、地高辛为OATP的底物。目前在中国人群中这2种药物的浓度与OATP基因多态性的相关性以及在中国使用上述2种药物的患病人群中该类基因的变异分布情况未知。这些信息可以为用药过程中的个体化差异提供依据。本项目组前期工作已经建立OATP基因的测序分析方法。本课题拟扩大样本量进行OATP基因筛查，获得健康人群和使用上述药物的患者基因变异的分布特征；在获得足够多基因突变例数的基础上，开展药代动力学的对比研究，以获得基因突变与药代动力学之间的关系；将TDM测得的血药浓度与基因分型信息相结合，获得OATP基因型与药物浓度的关系。

OATP是一类重要的摄入型转运体，对药物的吸收、分布、消除具有重要影响。本课题已经挑选出OATP基因的代表性位点，测定了上述位点在健康汉族人群及心力衰竭、风湿性关节炎患病人群的基因多态性分布特点；建立了稳定的高效液相色谱-质谱联用法测定风湿免疫病患者口服低浓度甲氨蝶呤的血药浓度；通过对临床患者的数据收集和血药浓度、基因型测定，统计分析了OATP基因多态性对地高辛谷浓度及甲氨蝶呤血药浓度的影响并建立群体药代动力学模型。研究结果显示OATP1B1 521T＞C突变型携带者地高辛谷浓度大于野生型携带者，P＜0.05；OATP1B3 699G＞A突变对甲氨蝶呤Css_max有微弱影响。该研究结果用于指导临床地高辛、甲氨蝶呤的个体化治疗，减少中毒等不良事件发生。