OCT2、MDR1基因多态性与婴幼儿万古霉素血药浓度及临床疗效的相关性研究
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摘要
目的:考察有机阳离子转运体2(OCT2)和多药耐药基因1(MDR1)的基因多态性与婴幼儿万古霉素稳态谷浓度及临床疗效的相关性。方法:收集91例万古霉素治疗的婴幼儿患者血样,酶免疫放大分析法测定万古霉素血药浓度,聚合酶链式反应(PCR)和DNA测序技术检测基因分型。比较OCT2 G808T(rs316019)和MDR1C3435T(rs1045642)不同基因型对万古霉素谷浓度及临床疗效的影响。结果:91例患者中,谷浓度达到10~20μg/mL的比例为16.5%;5~<10μg/mL和10~20μg/mL浓度范围万古霉素的临床有效率(88%,93.3%)显著高于5μg/mL以下浓度(44%)(P<0.05),同时5~<10μg/mL和10~20μg/mL浓度范围万古霉素的临床有效率相近。OCT2 G808T纯合突变型(TT)患者万古霉素谷浓度(10.15±2.35)μg/mL和谷浓度/剂量比(0.98±0.27)μg·mL~(-1)·mg~(-1)·kg均显著高于野生型(GG)患者(6.92±2.83)μg/mL和(0.59±0.22)μg·mL~(-1)·mg~(-1)·kg(P<0.05);同时,TT型患者临床有效率(100%)明显高于GG型(73.2%)(P<0.05);而MDR1 C3435T突变型和野生型患者的万古霉素谷浓度、谷浓度/剂量比及临床疗效相近(P>0.05)。结论:OCT2G808T基因突变可能与婴幼儿患者万古霉素的稳态谷浓度及临床疗效相关。
AIM: To study the effects of organic cation transporter 2( OCT2) and multidrug resistance gene 1( MDR1) gene polymorphisms on plasma concentration and clinical efficacy of vancomycin in infants. METHODS: Ninety-one infants that treated with vancomycin were recruited. The plasma concentrations of vancomycin were measured by enzyme multiplied immunoassay technique. The genotypes of OCT2 G808 T( rs316019) and MDR1 C3435 T( rs1045642) were determined by polymerase chain reaction followed with direct sequencing.The association between different genotypes and the concentrations and clinical efficacy of vancomycin were analyzed. RESULTS: There were 16. 5% patients which the concentration reached 10-20 μg/mL. The curative effect of 5-< 10 μg/mL( 88%)and 10-20 μg/mL( 93. 3%) were significant higher than that of < 5 μg/mL( 44%)( P < 0. 05); and the curative effect of 5-< 10 μg/mL and 10-20 μg/mL were similar. The plasma concentration( 10. 15± 2. 35) μg/mL and concentration/dose values( 0. 98 ± 0. 27) μg·mL~(-1)·mg~(-1)·kg of vancomycin in infants with OCT2 TT genotype were significantly increased than that of OCT2 GG genotypes( 6. 92 ±2. 83) μg/mL,( 0. 59 ± 0. 22) μg·mL~(-1)·mg~(-1)·kg( P < 0. 05). Meanwhile,the clinical efficacy of vancomycin in TT genotype( 100%) was higher than that in GG genotype( 73. 2%)( P < 0. 05).However,the concentration and clinical efficacy of vancomycin in the infants with mutant type and wild type of MDR1 C3435 T were similar( P > 0. 05).CONCLUSION: OCT2 G808 T polymorphism is associated with the plasma concentrations and clinical efficacy of vancomycin in infants.
AIM: To study the effects of organic cation transporter 2( OCT2) and multidrug resistance gene 1( MDR1) gene polymorphisms on plasma concentration and clinical efficacy of vancomycin in infants. METHODS: Ninety-one infants that treated with vancomycin were recruited. The plasma concentrations of vancomycin were measured by enzyme multiplied immunoassay technique. The genotypes of OCT2 G808 T( rs316019) and MDR1 C3435 T( rs1045642) were determined by polymerase chain reaction followed with direct sequencing.The association between different genotypes and the concentrations and clinical efficacy of vancomycin were analyzed. RESULTS: There were 16. 5% patients which the concentration reached 10-20 μg/mL. The curative effect of 5-< 10 μg/mL( 88%)and 10-20 μg/mL( 93. 3%) were significant higher than that of < 5 μg/mL( 44%)( P < 0. 05); and the curative effect of 5-< 10 μg/mL and 10-20 μg/mL were similar. The plasma concentration( 10. 15± 2. 35) μg/mL and concentration/dose values( 0. 98 ± 0. 27) μg·mL~(-1)·mg~(-1)·kg of vancomycin in infants with OCT2 TT genotype were significantly increased than that of OCT2 GG genotypes( 6. 92 ±2. 83) μg/mL,( 0. 59 ± 0. 22) μg·mL~(-1)·mg~(-1)·kg( P < 0. 05). Meanwhile,the clinical efficacy of vancomycin in TT genotype( 100%) was higher than that in GG genotype( 73. 2%)( P < 0. 05).However,the concentration and clinical efficacy of vancomycin in the infants with mutant type and wild type of MDR1 C3435 T were similar( P > 0. 05).CONCLUSION: OCT2 G808 T polymorphism is associated with the plasma concentrations and clinical efficacy of vancomycin in infants.
引文
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[9]抗菌药物临床试验技术指导原则写作组.抗菌药物临床试验技术指导原则[J].中国临床药理学杂志,2014,30(9):844-856.
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[11]Ye ZK,Chen YL,Chen K,et al.Therapeutic drug monitoring of vancomycin:a guideline of the division of therapeutic drug monitoring,chinese pharmacological society[J].J Antimicrob Chemother,2016,71(11):3020-3025.
[12]Chen J,Brockmoller J,Seitz T,et al.Tropane alkaloids as substrates and inhibitors of human organic cation transporters of the SLC22(OCT)and the SLC47(MATE)families[J].Biol Chem,2017,398(2):237-249.
[13]Yoon H,Cho HY,Yoo HD,et al.Influences of organic cation transporter polymorphisms on the population pharmacokinetics of metformin in healthy subjects[J].AAPS J,2013,15(2):571-580.
[2]Hou W,Zhang D,Lu W,et al.Polymorphism of organic cation transporter 2 improves glucose-lowering effect of metformin via influencing its pharmacokinetics in Chinese type 2 diabetic patients[J].Mol Diagn Ther,2015,19(1):25-33.
[3]Wolking S,Schaeffeler E,Lerche H,et al.Impact of genetic polymorphisms of ABCB1(MDR1,P-Glycoprotein)on drug disposition and potential clinical implications:update of the literature[J].Clin Pharmacokinet,2015,54(7):709-735.
[4]周源,卢雪玲,赵军,等.新疆维吾尔族人群SLC22A2中rs316019位点基因多态性分布研究[J].中国临床药理学与治疗学,2017,22(3):287-293.
[5]Christensen MM,Pedersen RS,Stage TB,et al.A gene-gene interaction between polymorphisms in the OCT2 and MATE1 genes influences the renal clearance of metformin[J].Pharmacogenet Genomics,2013,23(10):526-534.
[6]Amin ML.P-glycoprotein inhibition for optimal drug delivery[J].Drug Target Insights,2013,7:27-34.
[7]Sun H,Frassetto L,Benet LZ.Effects of renal failure on drug transport and metabolism[J].Pharmacol Ther,2006,109(1-2):1-11.
[8]付孟龙,周宏灏.MDR1基因多态性及其临床相关性[J].中国临床药理学与治疗学,2016,21(4):463-469.
[9]抗菌药物临床试验技术指导原则写作组.抗菌药物临床试验技术指导原则[J].中国临床药理学杂志,2014,30(9):844-856.
[10]张鞠玲,耿伟,崔恩博,等.肝硬化合并自发性细菌性腹膜炎病原学特征分析[J].临床肝胆病杂志,2015,31(3):407-412.
[11]Ye ZK,Chen YL,Chen K,et al.Therapeutic drug monitoring of vancomycin:a guideline of the division of therapeutic drug monitoring,chinese pharmacological society[J].J Antimicrob Chemother,2016,71(11):3020-3025.
[12]Chen J,Brockmoller J,Seitz T,et al.Tropane alkaloids as substrates and inhibitors of human organic cation transporters of the SLC22(OCT)and the SLC47(MATE)families[J].Biol Chem,2017,398(2):237-249.
[13]Yoon H,Cho HY,Yoo HD,et al.Influences of organic cation transporter polymorphisms on the population pharmacokinetics of metformin in healthy subjects[J].AAPS J,2013,15(2):571-580.