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首页> 外文期刊>Pharmacogenetics and genomics >CYP3A5*1/*3 genotype influences the blood concentration of tacrolimus in response to metabolic inhibition by ketoconazole.
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CYP3A5*1/*3 genotype influences the blood concentration of tacrolimus in response to metabolic inhibition by ketoconazole.

机译：CYP3A5 * 1 / * 3基因型对酮康唑的代谢抑制有影响，他克莫司的血药浓度。

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OBJECTIVES: Ketoconazole retards metabolic degradation of tacrolimus through its effect on the cytochrome P-450 enzyme system and allows reduction in treatment costs. Enzyme activity is determined by a single nucleotide polymorphism (*1/*3) in the CYP3A5 gene. METHODS: We prospectively investigated the impact of this polymorphism on tacrolimus concentration in a cohort of 79 renal transplant recipients on ketoconazole. Genotyping was carried out by using polymerase chain reaction-restriction fragment length polymorphism technique. Dose-adjusted trough level (C0) was calculated at baseline and at 3, 7, 15, 30, and 60 days. RESULTS: The baseline C0 was significantly lower in those with at least one *1 allele [44.95+/-14.12 vs. 63.43+/-14.72 (ng/ml)/(mg/kg/day), P<0.0001]. After starting ketoconazole in all genotypes, dose-normalized C0 increased and the cost of therapy decreased. Compared with baseline, the magnitude of increase was 112% and 79% in those without and with *1 allele, respectively (P<0.001). The cost savings were 32% and 39% in mycophenolate mofetil-treated and 47% and 61% in azathioprine-treated patients who were with and without one *1 allele, respectively. CONCLUSION: We show that the CYP3A5*1/*3 polymorphism is an important determinant of the response to inhibition of tacrolimus metabolism by ketoconazole, with a 30% greater inhibition in those lacking *1 allele. This finding will allow better dose adjustment and minimize exposure to subtherapeutic or toxic concentrations.
机译：目的：酮康唑可通过他克莫司对细胞色素P-450酶系统的作用来延缓他克莫司的代谢降解，并降低治疗成本。酶活性由CYP3A5基因中的单核苷酸多态性（* 1 / * 3）确定。方法：我们前瞻性地研究了这种多态性对酮康唑中79名肾移植受者队列中他克莫司浓度的影响。利用聚合酶链反应-限制性片段长度多态性技术进行基因分型。在基线以及第3、7、15、30和60天时计算剂量调整的谷值水平（C0）。结果：具有至少一个* 1等位基因的患者的基线C0显着降低[44.95 +/- 14.12与63.43 +/- 14.72（ng / ml）/（mg / kg / day），P <0.0001]。在开始使用所有基因型的酮康唑后，剂量标准化的C0增加，治疗费用降低。与基线相比，在没有* 1等位基因和有* 1等位基因的人群中，增加幅度分别为112％和79％（P <0.001）。接受麦考酚酯治疗的患者（分别有1个等位基因和没有* 1个等位基因）的成本节约分别为32％和39％，硫唑嘌呤治疗的患者分别节省47％和61％。结论：我们表明CYP3A5 * 1 / * 3多态性是酮康唑对他克莫司代谢抑制反应的重要决定因素，对缺乏* 1等位基因者的抑制作用大30％。这一发现将可以更好地调整剂量，并最大程度地减少亚治疗或毒性浓度的暴露。

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