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IF 4.7 2区医学 Q1 CHEMISTRY, MEDICINAL

Drug Design, Development and Therapy Pub Date : 2025-03-04 eCollection Date: 2025-01-01 DOI:10.2147/DDDT.S495647

Helin Xie, You Zheng, Hui Zhang, Yanmei Guo, Maobai Liu, Qinyong Weng, Xuemei Wu

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引用次数: 0

摘要

背景：由于复杂的临床条件和遗传因素，重症监护室（ICU）中机械通气（MV）患者对咪达唑仑（MDZ）的代谢存在很大差异。NR1I2 基因（PXR）编码一种核受体，可调节药物代谢酶（如 CYP3A4），在 MDZ 代谢中起着至关重要的作用。NR1I2 的多态性以及 CYP3A4、CYP3A5 和 ABCB1 等基因的变异可能会影响酶的活性和 MDZ 的药代动力学 (PK)。了解这些因素对于优化高危患者群体的 MDZ 剂量至关重要：我们研究了 61 名接受连续 MDZ 输注的重症监护病房患者。方法：我们研究了 61 名接受连续 MDZ 输注的重症监护病房患者，采用群体药代动力学（PopPK）模型评估 MDZ 的 PK，并评估遗传因素（NR1I2 rs2461817、CYP3A4、CYP3A5、ABCB1 和其他 PXR 多态性）和临床协变量（体重（BW）、天冬氨酸氨基转移酶（AST）水平）对 MDZ 清除率（CL）的影响：使用单室模型准确描述了MDZ及其代谢物1-羟基咪达唑仑（1-OH-MDZ）的PK。MDZ和1-OH-MDZ的CL的估计人群平均值分别为22.6升/小时（个体间差异[IIV]为59.4%）和67.1升/小时（个体间差异为57.7%）。MDZ CL与NR1I2 rs2461817多态性和谷草转氨酶水平有显著相关性，占变异性的11.3%。当谷草转氨酶从 22 IU/L 升高到 60 IU/L 时，MDZ CL 下降了 32.7%，而在 NR1I2 rs2461817 基因变异的患者中，MDZ CL 下降了 40.7%。体重也会影响 1-OH-MDZ 的 CL，当体重从 54 千克增加到 65 千克时，CL 会增加 34.2%。模拟证实了 NR1I2 rs2461817 对 MDZ CL 的显著影响：PopPK模型凸显了NR1I2 rs2461817多态性对中国中风患者MDZ CL的显著影响，强调了在ICU环境中优化MDZ剂量时需要考虑遗传和临床因素。

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Association of NR1I2 Polymorphism with Midazolam Clearance in Mechanically Ventilated ICU Patients: A Population Pharmacokinetic and Pharmacogenetic Study.

Background: Significant variability in the metabolism of midazolam (MDZ) exists among mechanically ventilated (MV) patients in the intensive care unit (ICU) due to complex clinical conditions and genetic factors. The NR1I2 gene (PXR), which encodes a nuclear receptor that regulates drug-metabolizing enzymes like CYP3A4, plays a critical role in MDZ metabolism. Polymorphisms in NR1I2, along with variations in genes such as CYP3A4, CYP3A5, and ABCB1, may influence enzyme activity and MDZ pharmacokinetics (PK). Understanding these factors is essential for optimizing MDZ dosing in high-risk patient populations.

Methods: We studied 61 MV ICU patients receiving continuous MDZ infusion. A population pharmacokinetic (PopPK) model was used to assess MDZ PK, with genetic factors (NR1I2 rs2461817, CYP3A4, CYP3A5, ABCB1, and other PXR polymorphisms) and clinical covariates (body weight (BW), aspartate aminotransferase (AST) levels) evaluated for their impact on MDZ clearance (CL).

Results: The PK of MDZ and its metabolite, 1-hydroxymidazolam (1-OH-MDZ), were accurately described using a one-compartment model. The estimated population means for MDZ and 1-OH-MDZ CL were 22.6 L/h (inter-individual variability [IIV] 59.4%) and 67.1 L/h (IIV 57.7%), respectively. MDZ CL was significantly associated with the NR1I2 rs2461817 polymorphism and AST levels, accounting for 11.3% of the variability. MDZ CL decreased by 32.7% as AST increased from 22 IU/L to 60 IU/L, and by 40.7% in patients homozygous for the NR1I2 rs2461817 variant. BW also influenced the CL of 1-OH-MDZ, demonstrating a 34.2% increase as weight increased from 54 kg to 65 kg. Simulations confirmed the significant impact of NR1I2 rs2461817 on MDZ CL.

Conclusion: The PopPK model highlights the significant impact of NR1I2 rs2461817 polymorphism on MDZ CL in Chinese MV patients, emphasizing the need to consider genetic and clinical factors for optimizing MDZ dosing in ICU settings.

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来源期刊

Drug Design, Development and Therapy CHEMISTRY, MEDICINAL-PHARMACOLOGY & PHARMACY

CiteScore

9.00

自引率

0.00%

发文量

382

审稿时长

>12 weeks

期刊介绍： Drug Design, Development and Therapy is an international, peer-reviewed, open access journal that spans the spectrum of drug design, discovery and development through to clinical applications. The journal is characterized by the rapid reporting of high-quality original research, reviews, expert opinions, commentary and clinical studies in all therapeutic areas. Specific topics covered by the journal include: Drug target identification and validation Phenotypic screening and target deconvolution Biochemical analyses of drug targets and their pathways New methods or relevant applications in molecular/drug design and computer-aided drug discovery* Design, synthesis, and biological evaluation of novel biologically active compounds (including diagnostics or chemical probes) Structural or molecular biological studies elucidating molecular recognition processes Fragment-based drug discovery Pharmaceutical/red biotechnology Isolation, structural characterization, (bio)synthesis, bioengineering and pharmacological evaluation of natural products** Distribution, pharmacokinetics and metabolic transformations of drugs or biologically active compounds in drug development Drug delivery and formulation (design and characterization of dosage forms, release mechanisms and in vivo testing) Preclinical development studies Translational animal models Mechanisms of action and signalling pathways Toxicology Gene therapy, cell therapy and immunotherapy Personalized medicine and pharmacogenomics Clinical drug evaluation Patient safety and sustained use of medicines.