遗传多态性对中东和北非地区苯妥英药代动力学和临床结局的影响。
Impact of Genetic Polymorphisms on Phenytoin Pharmacokinetics and Clinical Outcomes in the Middle East and North Africa Region.
机构信息
Faculty of Pharmaceutical Sciences, Pharmaceutical Sciences Building, University of British Columbia, Vancouver, BC, Canada.
College of Pharmacy, Qatar University, PO Box 2713, Doha, Qatar.
出版信息
Drugs R D. 2017 Sep;17(3):341-361. doi: 10.1007/s40268-017-0195-7.
BACKGROUND
Genetic polymorphisms are known to influence outcomes with phenytoin yet effects in the Middle East and North Africa region are poorly understood.
OBJECTIVES
The objective of this systematic review was to evaluate the impact of genetic polymorphisms on phenytoin pharmacokinetics and clinical outcomes in populations originating from the Middle East and North Africa region, and to characterize genotypic and allelic frequencies within the region for genetic polymorphisms assessed.
METHODS
MEDLINE (1946-3 May, 2017), EMBASE (1974-3 May, 2017), Pharmacogenomics Knowledge Base, and Public Health Genomics Knowledge Base online databases were searched. Studies were included if genotyping and analyses of phenytoin pharmacokinetics were performed in patients of the Middle East and North Africa region. Study quality was assessed using a National Institutes of Health assessment tool. A secondary search identified studies reporting genotypic and allelic frequencies of assessed genetic polymorphisms within the Middle East and North Africa region.
RESULTS
Five studies met the inclusion criteria. CYP2C9, CYP2C19, and multidrug resistance protein 1 C3435T variants were evaluated. While CYP2C9*2 and 3 variants significantly reduced phenytoin metabolism, the impacts of CYP2C192 and *3 variants were unclear. The multidrug resistance protein 1 CC genotype was associated with drug-resistant epilepsy, but reported impacts on phenytoin pharmacokinetics were conflicting. Appreciable variability in minor allele frequencies existed both between and within countries of the Middle East and North Africa region.
CONCLUSIONS
CYP2C9 decrease-of-function alleles altered phenytoin pharmacokinetics in patients originating from the Middle East and North Africa region. The impacts of CYP2C19 and multidrug resistance protein 1 C3435T variants on phenytoin pharmacokinetic and clinical outcomes are unclear and require further investigation. Future research should focus on the clinical outcomes associated with phenytoin therapy. PROSPERO 2017: CRD42017057850.
背景
已知遗传多态性会影响苯妥英的疗效，但中东和北非地区的相关影响仍知之甚少。
目的
本系统评价的目的是评估遗传多态性对来自中东和北非地区人群苯妥英药代动力学和临床结局的影响，并描述该地区评估的遗传多态性的基因型和等位基因频率。
方法
检索 MEDLINE（1946 年 3 月 5 日至 2017 年 3 月 5 日）、EMBASE（1974 年 3 月 5 日至 2017 年 3 月 5 日）、药物基因组学知识库和公共卫生基因组学知识库在线数据库。纳入对中东和北非地区患者进行基因分型和苯妥英药代动力学分析的研究。使用美国国立卫生研究院评估工具评估研究质量。二次检索确定了报告中东和北非地区评估遗传多态性的基因型和等位基因频率的研究。
结果
符合纳入标准的研究有 5 项。评估了 CYP2C9、CYP2C19 和多药耐药蛋白 1 C3435T 变异。虽然 CYP2C9*2 和 3 变异显著降低了苯妥英的代谢，但 CYP2C192 和 *3 变异的影响尚不清楚。多药耐药蛋白 1 CC 基因型与耐药性癫痫有关，但报告的对苯妥英药代动力学的影响存在冲突。中东和北非地区各国之间以及各国内部的次要等位基因频率存在显著差异。
结论
来自中东和北非地区的患者中，CYP2C9 功能降低等位基因改变了苯妥英的药代动力学。CYP2C19 和多药耐药蛋白 1 C3435T 变异对苯妥英药代动力学和临床结局的影响尚不清楚，需要进一步研究。未来的研究应集中在与苯妥英治疗相关的临床结局上。PROSPERO 2017：CRD42017057850。
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