研究埃及肝移植患者体内代谢酶的单核苷酸多态性与钙调磷酸酶抑制剂治疗血清水平之间的关系

IF 3.4 Q2 PHARMACOLOGY & PHARMACY
Nermeen N. Abuelsoud, Mohamed Bahaa, Sara A. Osman, Nouran Younis, Mohamed M. Kamal
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引用次数: 0

摘要

背景许多临床变量都可能影响钙调磷酸酶抑制剂(CIs)的药代动力学。细胞色素 P450 (CYP)3A4/5 和药物转运体 P-glycoprotein 的不同等位基因是主要变量。其他变量包括移植类型、移植后的治疗时间、年龄、性别、饮食习惯、所用药物以及肝肾功能损害。他克莫司和环孢素是器官移植中广泛使用的两种主要 CIs。这两种药物均由 CYP3A4 和 CYP3A5 同工酶代谢,这些基因的单核苷酸多态性已被证明会影响 CIs 的药代动力学。另一个重要基因是孕烷 X 受体(PXR),它管理着包括 CYP3A4 基因在内的多种基因的声明。PXR 在 CIs 代谢中具有临床意义。肝脏是 CIs 代谢的重要场所。与肝功能正常的患者相比,肝功能受损患者的 CIs 清除率降低,半衰期延长。不同的遗传和临床因素可能会影响钙神经蛋白抑制剂的谷值水平,从而影响其在肝移植后的免疫抑制效果。本研究旨在确定 CYP3A4 1B rs2740574 和 PXR A7635G rs6785049 的不同基因多态性及其他可能影响肝移植后钙调素抑制剂药代动力学的临床因素的影响。结果 CYP3A4 基因中 T 等位基因的存在与他克莫司剂量为 4、30、60 和 90 后的 DATL 升高相关,P 值分别为 0.00、0.00、0.007 和 0.00。关于 PXR 基因,G 等位基因的存在与环孢素的 DATLs 升高有关。在这两种药物中检测了约 432 个相关基因。在 CYP3A4 基因型 CC 中,男性性别与 DATLs 升高有关,两者呈强正相关,除 DATL 60 外,所有 DATLs 的差异均有统计学意义(P 值为 0.374)。在几乎所有随访期间,都没有发现血红蛋白水平低与 DATLs 之间有很强的关联。结论研究可能影响钙神经蛋白酶抑制剂血清浓度的各种遗传学和临床因素对于器官移植后的成功治疗计划非常重要。这些不同的因素可能会相互影响,而这些复杂的相互作用可能会使患者移植后的病情复杂化。考虑到所有这些复杂的相互作用对于监测治疗计划至关重要,尤其是在存在其他合并症或慢性疾病的情况下。应针对大量患者开展更多研究,以探索这些患者治疗计划中的这些相互作用变量的更多后果,并且在监测移植后患者时应考虑本研究中的所有参数。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Studying the association between single nucleotide polymorphisms of metabolizing enzymes and the therapeutic serum levels of calcineurin inhibitors in Egyptian liver transplant patients

Background

Many clinical variables might impact the pharmacokinetics of calcineurin inhibitors (CIs). Different alleles of cytochromes P450 (CYP)3A4/5 and drug transporter P-glycoprotein are the main variables. Other variables include relocated type, treatment duration after transplantation, age, sex, dietary consumption, medications used and renal or hepatic impairment. Tacrolimus and cyclosporine are two main CIs extensively used in organ transplantation. Both drugs are metabolized by CYP3A4 and CYP3A5 isoforms, and single-nucleotide polymorphisms in these genes have been displayed to influence CIs pharmacokinetics. Another important gene is the pregnane X receptor (PXR), which manages the statement of a variety of genes including CYP3A4 genes. PXR has a clinical significance in CIs metabolism. The liver is the essential site for CIs metabolism. A decreased clearance with a prolonged CIs half-life was occurred in patients with impaired liver compared with patients with normal liver function. The presence of different genetic and clinical factors that may affect calcineurin inhibitors trough levels will consequently affect their immunosuppressant effect after liver transplantation.

Purpose

This study aims to determine the effect of different genetic polymorphisms in CYP3A4 1B rs2740574 and PXR A7635G rs6785049 and other clinical factors that may affect calcineurin inhibitors pharmacokinetics after liver transplantation.

Results

The presence of T allele in CYP3A4 gene was associated with elevated DATLs with P values of 0.00, 0.00, 0.007 and 0.00 after tacrolimus doses 4, 30, 60 and 90, respectively. Regarding PXR gene, the presence of G allele was associated with elevated DATLs in cyclosporine. About 432 correlations were tested in both drugs. In CYP3A4 genotype CC, male sex was associated with elevated DATLs interpreted by strong positive correlations and statistically significant difference in all DATLs, except DATL 60 (P value 0.374). No strong association was found between low hemoglobin levels and DATLs in almost all the follow-up periods. There were many positive relations between increased total and direct bilirubin and increased DATLs.

Conclusions

Studying the various genetics and clinical factors that may affect calcineurin inhibitors serum concentrations is very essential for successful treatment plans after organ transplantation. These different factors may interact with each other and these complicated interactions may complicate the patient’s conditions post-transplantation. Considering all these complicated interactions is very crucial in monitoring treatment plans, especially in the presence of other comorbidities or chronic diseases. More studies with large number of patients should be conducted to explore more consequences of these interacting variables of treatment plans of these patients and all studied parameters in this study should be considered while monitoring patients after transplantation.

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来源期刊
自引率
0.00%
发文量
44
审稿时长
23 weeks
期刊介绍: Future Journal of Pharmaceutical Sciences (FJPS) is the official journal of the Future University in Egypt. It is a peer-reviewed, open access journal which publishes original research articles, review articles and case studies on all aspects of pharmaceutical sciences and technologies, pharmacy practice and related clinical aspects, and pharmacy education. The journal publishes articles covering developments in drug absorption and metabolism, pharmacokinetics and dynamics, drug delivery systems, drug targeting and nano-technology. It also covers development of new systems, methods and techniques in pharmacy education and practice. The scope of the journal also extends to cover advancements in toxicology, cell and molecular biology, biomedical research, clinical and pharmaceutical microbiology, pharmaceutical biotechnology, medicinal chemistry, phytochemistry and nutraceuticals.
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