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首页> 外文期刊>Basic & clinical pharmacology & toxicology. >CYP3A5*3 CYP3A5*3 and ABCB1 ABCB1 61A>G Significantly Influence Dose‐adjusted Trough Blood Tacrolimus Concentrations in the First Three Months Post‐Kidney Transplantation
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CYP3A5*3 CYP3A5*3 and ABCB1 ABCB1 61A>G Significantly Influence Dose‐adjusted Trough Blood Tacrolimus Concentrations in the First Three Months Post‐Kidney Transplantation

机译：CYP3A5 * 3 CYP3A5 * 3和ABCB1 ABCB1 61A> G显着影响肾上前三个月的剂量调整的槽血巨蜥浓度

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Abstract Tacrolimus (TAC) is a first‐line immunosuppressant used to prevent organ rejection after kidney transplantation. There is large inter‐individual variability in its pharmacokinetics. Single nucleotide polymorphisms (SNPs) in genes encoding TAC metabolizing enzymes cytochromes P450 3A4/5 ( CYP3A4/5 ), P‐glycoprotein efflux transporter ( ABCB1 ), their expression regulator pregnane X receptor ( NR1I2 ) and CYP3A co‐factor cytochrome P450 reductase ( POR ) have been studied for their effects on tacrolimus disposition. However, except for CYP3A5*3 , controversies remain about their roles in predicting dose‐adjusted trough blood TAC concentrations (C 0 /D). This study aimed to investigate the effects of ABCB1 (61AG, 1199GA, 1236CT, 2677GT and 3435CT), CYP3A4*22 , CYP3A5*3 , NR1I2 (8055CT, 63396CT and ‐25385CT) and POR*28 SNPs on TAC C 0 /D. In total, 165 kidney transplant recipients were included in this study. SNPs were genotyped by probe‐based real‐time polymerase chain reaction. Associations between log‐transformed whole blood TAC C 0 /D (measured at 1 and 3 months post‐transplant) and genotypes/haplotypes were assessed by linear mixed effects analysis, controlling for age, sex and haematocrit. It was observed that CYP3A5 expressors ( *1/*1 + *1/*3 ) ( p = 5.5 × 10 ?16 ) and ABCB1 61G allele carriers ( p = 0.001) had lower log‐transformed TAC C 0 /D (56% and 26% lower geometric mean TAC C 0 /D, respectively) and accounted for approximately 30% and 4%, respectively, of log‐transformed TAC C 0 /D variability in the first 3 months post‐transplant. In conclusion, CYP3A5*3 is a major, and ABCB1 61AG is a novel, although minor, genetic factor affecting TAC C 0 /D in kidney transplant recipients.
机译：摘要Tacrolimus（TAC）是一种用于预防肾移植后器官排斥的一线免疫抑制剂。其药代动力学具有大的间间变异性。单核苷酸多态性（SNP）在编码TAC代谢酶的基因中细胞学P450 3A4 / 5（CYP3A4 / 5），P-糖蛋白排出转运蛋白（ABCB1），其表达调节剂妊娠X受体（NR1I2）和CYP3A共同因子细胞色素P450还原酶（ POR已经研究了它们对他克莫司处理的影响。然而，除Cyp3a5 * 3外，仍然存在于预测剂量调节的槽血液TAC浓度（C 0 / D）中的作用。本研究旨在探讨ABCB1（61A＆ G，1199G＆GT; A，1236C＆ T，2677g＆ t，2677g＆ t，Cyp3a5，Cyp3a5 * 3，NR1i2（8055C＆ t，63396c＆ t和 - 25385c＆ t）和por * 28 snps在tac c 0 / d上。总共包括165个肾移植受者，包括在本研究中。 SNP通过基于探针的实时聚合酶链反应进行基因分型。通过线性的混合效应分析评估对数转化的全血TAC C 0 / D（在移植后1和3个月测量）和基因型/单倍型测量的关联，控制年龄，性别和血细胞比容。被观察到CYP3A5表达器（* 1 / * 1 + * 1 / * 3）（P = 5.5×10？16）和ABCB1 61G等位基因载体（P = 0.001）具有较低的对数转换TAC C 0 / D（56分别为几何平均TAC C 0 / D的％和26％，分别占移植后的前3个月的对数转化的TAC C 0 / D变异的约30％和4％。总之，CYP3A5 * 3是一个主要的，ABCB1 61A＆GT; G是一种新颖的，虽然肾移植受者中的次要遗传因素，但在肾移植受者中影响TAC C 0 / D。

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