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近年来随着医药行业的快速发展,治疗药物监测愈益成为临床药物治疗工作的一项重要内容,也是个体化用药指导的重要手段之一。治疗药物监测[1](therapeutic drug monitoring,TDM),其目的是通过测定血液中或其他体液中药物的浓度并利用药动学的原理相应调整药物剂量,使给药方案个体化,以提高药物的疗效,避免或减少毒副反应;同时也为药物过量中毒的诊断和处理提供实验室依据,简而言之就是对药物浓度的评估[2]。药物治疗窗(therapeutic drug window)指药物产生最小治疗效应与机体能耐受的最小中毒反应间的血药浓度范围,是TDM的临床用药依据。目前临床上开展TDM的药物涉及多种类、多监测方法,但TDM的治疗窗和血样却没有很好的分析、归纳及总结。前期课题组研究表明[3-4],高原环境对药物代谢酶、转运体的活性及蛋白表达均有一定的影响,导致高原环境下药动学参数发生变化,而药动学参数是指导临床合理用药的重要理论依据,直接关系到给药的剂量及给药时间,那么高原低氧环境对临床常用监测药物的代谢是否会产生影响?本文将对临床上常用的治疗监测药物种类、治疗窗、以及检测血样进行归纳和总结,分析高原环境下对临床常用监测药物代谢的影响,一方面有利于指导临床合理用药、毒性反应评估、引导个体化用药;另一方面,为本课题组进一步研究高原环境下开展TDM提供理论指导。
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随着TDM研究的不断深入,王菁等人[5]归纳了临床上遴选TDM遵循的八条原则。即行TDM的药物具有自身治疗指数低、治疗窗窄、毒性较大、非线性药动学特征和个体差异较大,以及联合用药时会发生相互作用,导致血药浓度变化等特点。目前,需TDM的药物种类主要包括免疫抑制剂,如他克莫司(FK506)、环孢霉素(CsA);抗菌药,如万古霉素、替考拉宁;平喘药,如氨茶碱;抗癫痫药,如丙戊酸(VPA)、卡马西平(CBZ)、苯巴比妥;心血管系统药物,如地高辛;抗心律失常药物,如普鲁卡因胺、利多卡因、奎尼丁;抗肿瘤药,如甲氨蝶呤(MTX);抗抑郁药,如丙咪嗪、阿米替林、碳酸锂,等等。由于这些药物个体差异大,容易在同等剂量出现毒副反应或达不到相应的疗效,因此,临床上需要做TDM。使监测药物的血药浓度控制在治疗窗内,是保证患者安全、有效的用药关键。以下将临床上常用TDM药物的治疗窗及血样进行分类(表1)。
表 1 临床常用治疗监测药物的治疗窗
类别 代表药物 血样 治疗窗 免疫抑制剂 他克莫司 全血 5−10 ng/ml 环孢霉素 全血 150−400 ng/ml 抗菌药 万古霉素 血清 10−15 μg/ml 替考拉宁 血浆 ρmin≥10 μg/ml(非复杂感染) 20−60 μg/ml(深部复杂感染) 平喘药 氨茶碱 血清 10−20 mg/ml 血浆 55−110 μmol/L 抗癫痫药 丙戊酸 血清 50−100 μg/ml 苯巴比妥 血清 10−40 μg/ml 卡马西平 血清 4−12 μg/ml 心血管系统药物 地高辛 血清 0.8−2.0 ng/ml 并非所有的药物都需要做血药浓度监测,一些有显著效果指标的药物,如降压药(如硝苯地平、厄贝沙坦、卡托普利等),其临床的治疗效果可以直接通过测定患者血压数值来反映降压的程度,进而根据血压数值调整用药的剂量;新型广谱唑类药物艾沙康唑(isavuconazole)目前也不需要TDM[6]。对于上述治疗窗宽、安全范围广的药物进行血药浓度监测和药代动力学参数的研究并没有多少实际意义。
进行监测的药物血样[7]主要有全血、血浆及血清等,监测血样的确定主要根据药物与血浆蛋白、红细胞结合率,以及游离状态来决定,以便更好的评价血药浓度,指导临床个体用药剂量。当药物主要与血液中红细胞结合时,监测的血样一般选择全血;药物与血浆蛋白结合率高时,主要以游离态来发挥作用时,选择血清为监测的血样结果会更加准确。例如,免疫抑制剂他克莫司、环孢霉素,监测的血样为全血,因为多数他克莫司与血液中红细胞结合,少数与血浆中的脂蛋白结合[8-9];环孢霉素也在血浆中与血浆蛋白和红细胞的结合率高[10]。由于他克莫司、环孢霉素与红细胞有较高的结合率,因此,必须以全血为血样,以保证监测的浓度结果更加可靠、准确、稳定,但在测定全血时干扰物质较多,全血处理也要有严格的要求[雅培公司所产的全自动免疫分析仪(型号:AR i1000SR)在测定血样前需加入全血沉淀试剂];而抗癫痫药丙戊酸的监测血样为血清,因为丙戊酸80%~90%处于与血浆蛋白结合状态,主要以游离态发挥作用[11],因此,丙戊酸以血清来评价血药浓度。研究表明[12],在血清中加入适量的高丰度蛋白质去除试剂乙腈,不仅能够有效沉淀蛋白,减少对血药浓度的影响,还能减弱加入内标提取液引起的乳化现象,使临床监测更加简便、经济。
Advances in research on the impact of the plateau environmental on the drug metabolism
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摘要: 高原环境会影响药物在体内的代谢,使得药动学参数、药物代谢酶及转运体的表达及功能均会发生变化。随着医药行业的快速发展,治疗药物监测(TDM)作为个体化用药的依据被广泛的关注,高原环境对监测药物有何影响?笔者通过查阅国内外相关文献,对临床上常用的治疗监测药物种类、治疗窗以及检测血样进行了归纳和总结,分析高原低氧环境对临床常用监测药物代谢的影响。为高原临床治疗药物监测提供参考,更好的保证高原人群合理用药,也为后期课题组开展高原治疗药物监测以及研究药物的遴选提供参考。Abstract: Plateau environment will affect the metabolism of drugs in the body, which will cause changes in pharmacokinetic parameters, expression and function of drug metabolizing enzymes and transporters. With the rapid development of the pharmaceutical industry, therapeutic drug monitoring (TDM) has been widely paid attention to as a basis for personalized drugs. What impact does the plateau environment on monitoring drugs? In this literature review, we will summarize the types of commonly used therapeutic monitoring drugs, therapeutic windows, and blood samples, analyze the effects of plateau hypoxic environment on the metabolism of commonly used monitoring drugs, provide a reference for the clinical treatment and monitoring drugs of plateau, better ensure the rational use of drugs in the plateau population, and also provide a reference for the later research group to conduct the monitoring of plateau therapeutic drugs and the selection of research drugs.
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Key words:
- therapeutic drug monitoring /
- therapeutic window /
- drug metabolism /
- plateau hypoxia /
- rational use
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表 1 临床常用治疗监测药物的治疗窗
类别 代表药物 血样 治疗窗 免疫抑制剂 他克莫司 全血 5−10 ng/ml 环孢霉素 全血 150−400 ng/ml 抗菌药 万古霉素 血清 10−15 μg/ml 替考拉宁 血浆 ρmin≥10 μg/ml(非复杂感染) 20−60 μg/ml(深部复杂感染) 平喘药 氨茶碱 血清 10−20 mg/ml 血浆 55−110 μmol/L 抗癫痫药 丙戊酸 血清 50−100 μg/ml 苯巴比妥 血清 10−40 μg/ml 卡马西平 血清 4−12 μg/ml 心血管系统药物 地高辛 血清 0.8−2.0 ng/ml -
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