CYP3A5*3基因变异对突尼斯肾移植受者他克莫司药代动力学及预后的影响。
The effects of the CYP3A5*3 variant on tacrolimus pharmacokinetics and outcomes in Tunisian kidney transplant recipients.
作者信息
Charfi Rim, Bacha Mohamed Mongi, Ben Fadhal Myriam, Ferchichi Khouloud, El Jebari Hanene, Gaies Emna, Klouz Anis, Abderrahim Ezzeddine, Ben Hamida Fathi, Ben Abdallah Taieb, Trabelsi Sameh, Gorgi Yosr, Sfar Imen
机构信息
University of Tunis El Manar, Faculty of de Medicine of Tunis. National Centre Chalbi Belkahia of Pharmacovigilance, Department of clinical pharmacology, Research Laboratory of Clinical and Experimental Pharmacology (LR16SP02), 1006 Tunis, Tunisia.
Charles Nicolle hospital -Department of nephrology and internal medicine, Research Laboratory of Renal Pathology (LR00SP01), 1006 Tunis, Tunisie.
出版信息
Tunis Med. 2023 Oct 5;101(10):738-744.
INTRODUCTION
Tacrolimus, exhibits interindividual pharmacokinetic variability and a narrow therapeutic index. The influence of the CYP3A5 6986A>G single nucleotide polymorphism (SNP) on this variability remains a topic of debate.
AIM
To assess the impact of the aforementioned SNP on tacrolimus area under curve (AUC0-12h), adverse drug reactions (ADRs), and kidney graft outcomes.
METHODS
Blood samples were collected from Tunisian kidney transplants over a five-year period during either the early (<3 months) or late (>3 months) post-transplant phases. Through blood concentration (C0) and AUC0-12h of tacrolimus were measured. Patients were prospectively followed to assess graft outcomes. Polymerase chain reaction of restriction fragment length polymorphism was used for CYP3A5 6986A>G genotyping.
RESULTS
Fifty Tunisian kidney recipients receiving tacrolimus were enrolled in the study. Acute and chronic graft rejections were observed in eight and three patients, respectively. Twenty-one patients (42%) reported ADRs. C0 and AUC0-12h, showed a significant difference between CYP3A51 carriers (mean C0=4 ng.mL-1 and AUC0-12h=94.37 ng.h.mL-1) and CYP3A53/3 or poor metabolizers carriers (mean C0=7.45 ng.mL-1; AUC0-12h=151.27 ng.h.mL-1) (p=0.0001; p=0.003, respectively). Supratherapeutic tacrolimus levels were significantly more common in poor metabolizers (p=0.046; Odds-ratio =1.3; confidence interval 95% [1.12-1.66]). The impact of SNP was significant on C0, AUC0-12h, C0/Dose and AUC0-12h/Dose, only in the late phase (p=0.01, 0.002, 0.012, 0.003 respectively).
CONCLUSION
CYP3A5*3 variant was significantly associated with tacrolimus pharmacokinetics but had no impact on graft outcomes.
引言
他克莫司存在个体间药代动力学变异性且治疗指数较窄。细胞色素P450 3A5（CYP3A5）6986A>G单核苷酸多态性（SNP）对这种变异性的影响仍是一个有争议的话题。
目的
评估上述SNP对他克莫司曲线下面积（AUC0 - 12h）、药物不良反应（ADR）及肾移植结局的影响。
方法
在五年期间从突尼斯肾移植受者中收集血样，时间为移植后早期（<3个月）或晚期（>3个月）。测定他克莫司的血药浓度（C0）及AUC0 - 12h。对患者进行前瞻性随访以评估移植结局。采用聚合酶链反应 - 限制性片段长度多态性方法进行CYP3A5 6986A>G基因分型。
结果
50名接受他克莫司治疗的突尼斯肾移植受者纳入本研究。分别有8例和3例患者发生急性和慢性移植排斥反应。21例患者（42%）报告有药物不良反应。CYP3A51携带者（平均C0 = 4 ng/mL且AUC0 - 12h = 94.37 ng·h/mL）与CYP3A53/3或代谢不良者携带者（平均C0 = 7.45 ng/mL；AUC0 - 12h = 151.27 ng·h/mL）之间的C0及AUC0 - 12h显示出显著差异（p分别为0.0001；0.003）。他克莫司血药浓度高于治疗水平在代谢不良者中显著更常见（p = 0.046；比值比 = 1.3；95%置信区间[1.12 - 1.66]）。仅在晚期，SNP对C0、AUC0 - 12h、C0/剂量及AUC0 - 12h/剂量有显著影响（p分别为0.01、0.002、0.012、0.003）。
结论
CYP3A5*3变异与他克莫司药代动力学显著相关，但对移植结局无影响。
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