世界品牌女包排名


研究论文药理学DOI:10.1159 / 000510327

收到:2020年5月28日接受:2020年7月20日在线发布:2020年9月30日

FMO3变体对口服伏立康唑在发热性中性粒细胞减少症中的血浆处置和口服伏立康唑不良反应的预测价值肖康,王静,赵静,丁文,薛学,廖安,罗斌,b

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aDepartment

深圳市龙华区中心医院药房b广东省妇幼医院药剂科,广州; c华中科技大学同济医学院附属武汉精神卫生中心药理教研室,武汉

摘要背景与目的:随着发热性中性粒细胞减少症(FN)患者的增多,伏立康唑(VRC)已在医院中广泛用于FN的一线治疗。该研究旨在评估FMO3突变对FN中VRC的血浆分布和不良反应的影响。材料和方法:在住院病房进行了为期4年的单中心观察性研究。通过PCR限制性片段长度多态性检测FMO3和细胞色素P450(CYP)2C19的基因型。根据CYP2C19代谢表型和其他纳入标准筛选中性粒细胞减少症患者。实验性施用VRC后五天,通过液相色谱电喷雾串联质谱法(LC-ESI MS / MS)测定患者血液中的VRC和氮氧化物的血药浓度。收集病历中的血清参数和临床不良反应症状并进行统计分析。结果:共有165例中性粒细胞减少症患者

[email protected] www.karger.com/pha

? 2020 S. Karger AG, Basel

the intermediate metabolic phenotype of CYP2C19 were screened. At the initial stage of oral VRC treatment, patients with the FMO3 E308G genotype had a poorer plasma disposal ability to VRC than those with the wide type of FMO3 (WT) genotype (p = 0.0005). Moreover, patients with the FMO3 E308G genotype were more likely to have adverse drug reactions and abnormal serum parameters after receiving VRC treatment. For example, the serum potassium level in the FMO3 E308G genotype group was significantly lower than that in the WT group (p = 0.028), the abnormal level of total bilirubin in the FMO3 E308G genotype group was significantly higher than that in the WT group (p = 0.049), and the aspartate aminotransferase level in the E308G group was significantly higher than that in the WT group (p = 0.05). The incidence of atopic dermatitis and visual impairment in the FMO3 E308G genotype group was 67 and 75%, respectively, and the incidences of peripheral neuroedema, headache, and diarrhea were 57, 50, and 60%, respectively, which were significantly different from those in the WT group. Conclusion: FMO3 E308G reduces the activity of the FMO3 enzyme by decreasing the metabolic ability of VRC, which increases the plasma concentration of VRC and may also lead to adverse reactions in patients with FN. ? 2020 S. Karger AG, Basel

Xiaokang Wang Department of Pharmacy, Shenzhen Longhua District Central Hospital No. 187 Western Guanlan Avenue Shenzhen 518110 (China) kangtae.wang @ yahoo.com

下载者:奥克兰理工大学156.62.3.11-2020年10月6日4:36:09 AM

Keywords Voriconazole · E308G · Febrile neutropenia · Genetic · Adverse effect

介绍

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药理学DOI:10.1159 / 000510327

F

F

N

CYP / FMO

N N

F

F

N

伏立康唑

N

N

N + O–

伏立康唑N-氧化物

图1. VRC肝脏代谢途径及其代谢产物。 CYP和FMO是VRC在代谢过程中的主要代谢酶。 CYP,细胞色素P450; FMO,含黄素的单加氧酶; VRC,伏立康唑。

nificant correlation between plasma disposition of VRC and the incidence of adverse reactions [15]. When the clinical dosage is the same, the plasma disposal ability of VRC is determined by the pharmacokinetic characteristics of specific patients. The pharmacokinetics of VRC shows a large variability that depends on drug-drug interactions, inflammation, and drug metabolic enzyme gene polymorphism [16]. Therefore, according to the above paragraph, interindividual variability in the expression of FMO3 may affect drugs and xenobiotics in the liver. Early clinical reports have shown that many polymorphisms of FMO3, especially those at the E158K and E308G loci, lead to amino acid substitution that changes the affinity for specific substrates, thus resulting in individual differences in therapy efficacy and safety of VRC [17, 18]. From the research over the past decade, the main gene frequencies of the Han population are E158K (0.229), V257M (0.203), and E308G (0.148) [19]. Studying which variation of the FMO3 gene might affect the ability of individuals to deal with the variety of VRC products that are substrates for FMO3 is of great need. Materials and Methods Study Population and Schedule This observational, single-center, and retrospective study was conducted from January, 2016, to December, 2019, at the Shenzhen Longhua District Central Hospital. All adult patients were tested for CYP2C19 genotypes before grouping, and those who received chemotherapy for either hematological or solid malignancies were screened for enrollment. Of these patients who fulfilled all of the following criteria for both clinical and laboratory diagnoses of FN were included in this study. FN was defined as a neutrophil count 40 IU L?1), and ALT (>50 IU L?1) were evaluated for diagnosing hepatotoxicity during the VRC treatment. Serum potassium concentration (38°C for >1 h [12]. The course of oral treatment with VRC lasts at least 5 days, and each patient is given a dose strictly in accordance with the drug instructions, twice daily. The exclusion criteria were as follows: (1) patients who were under 16 years of age, (2) patients who received a combination of CYP2C19 or CYP3A4 potent modulators (including rifampicin, ritonavir, or carbamazepine, a long-acting barbiturate, or a macrolide antibiotic), (3) patients with hypokalemia (serum potassium 34.2 μmol L?1), (6) patients with a chronic active inflammatory disease (C-reactive protein >5 mg dL?1), and (7) patients with poor compliance with respect to their medications based on electronic medical records. Blood samples (2 mL) were collected for the first time before administration on or after 5 days after the start of VRC therapy.

表1. FN患者的临床特征和人口统计学

变量

WT的值

Demographic data Age, years 48 (26–85) Sex, male 34 (52) BMI 22.05 (17.6–28.4) Underlying condition Hematological malignancy 45 (68) Solid-organ transplantation 3 (4.5) Abdominal surgery 1 (1.5) Chronic liver disease 3 (4.5) Other condition 5 (7.5) None 9 (14) Oral VRC therapy 66 VRC daily dose, mg day?1 200 (200–400) Duration of therapy, days 20 (7–45)

E158K

E308G

V257M

49 (27–82) 15 (45) 22.3 (19.6–26.4)

47 (24–80) 16 (47) 21.45 (18.5–25.9)

48 (28–82) 16 (50) 21.3 (17.6–24.5)

24 (73) 2 (6.1) 0 1 (3) 2 (6.1) 4 (11.8) 33 200 (200–400) 20.5 (10–46)

26 (76.5) 2 (6) 0 2 (6) 1 (5.5) 2 (6) 34 200 (200–400) 21 (12–48)

23 (72) 4 (12.5) 1 (3.1) 3 (9.3) 0 1 (3.1) 32 200 (200–400) 21.5 (10–45)

p = 0.0005

3

2

1

0

WT (n = 15)

E158K E308G (n = 10) (n = 6) Genotypes

V257M (n = 7)

Fig. 3. FMO3 polymorphisms on VRC trough concentrations adjusted on the dose (VRC Cmin/D). Influence of FMO3 genotypes on VRC Cmin/D ratio obtained during VRC oral treatment. Data are presented as IQR (boxes), data range (whiskers), and median (horizontal line). Significant p value was obtained by the t test. Data are expressed as mean ± SD. ***p < 0.001 versus the WT group. VRC, voriconazole; WT, wide type of FMO3; IQR, interquartile range.

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结果

患者特征研究的选择程序和分组如图2所示。诊断为中性粒细胞减少的患者按CYP2C19基因型分类(在线补充表2)。我们通过医疗记录确定了365个潜在相关记录。根据患者意愿的筛选和实验纳入标准,排除了191位非中间代谢表型患者,并保留了165位具有中间代谢物的患者进行受试者评估。共有165例患者接受了口服VRC治疗。根据FMO3基因型对这些患者进行分组,并获得了下表(在线补充表3)。所有患者均口服VRC片剂,这些患者的其他临床和人口统计学特征汇总于表1。FMO3多态性对血浆VRC谷浓度的影响在VRC口服治疗期间,当患者出现严重不良反应(如复视,将及时监测血药浓度,以指导剂量调整治疗。在这项研究中,有38例患者在治疗初期出现了严重的不良反应,并监测了他们的VRC血清浓度。研究了FMO3多态性对Wang / Zhao / Wen / Liao / Luo的影响

下载者:奥克兰理工大学156.62.3.11-2020年10月6日4:36:09 AM

等离子VRC Cmin / D,103 L–1

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彩色版本可在线获得

FN,发热性中性粒细胞减少; VRC,伏立康唑; WT,FMO3的宽类型; IQR,四分位间距。 a数据表示为中位数(IQR)或n(%)。

Total bilirubin concentration, μmol L–1

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3

2

1

a

WT (n = 66)

天冬氨酸转氨酶,IU L–1

100

80

E158K E308G (n = 33) (n = 34) Genotypes

V257M (n = 32)

b

40

20

世界品牌女包排名 E158K E308G (n = 33) (n = 34) Genotypes

WT (n = 66)

E158K E308G (n = 33) (n = 34) Genotypes

V257M (n = 32)

WT (n = 66)

E158K E308G (n = 33) (n = 34) Genotypes

V257M (n = 32)

80

p = 0.047

WT (n = 66)

50

0

p = 0.03

60

0

p = 0.049

100

V257M (n = 32)

60

40

20

0

d

图4. VRC诱导的异常血清参数患者的临床和遗传特征。从病历中收集每位患者的最低血清钾浓度和最大TB浓度。比较了不同基因型的FMO3的最低血清钾浓度。 b比较了不同基因型的FMO3的最大TB浓度。 c,d FMO3基因型对AST和ALT水平的影响。数据显示为IQR(框),数据

range (whiskers), and median (horizontal line). Significant p value was obtained by the t test and is shown above. Standard serum potassium concentration: 3.5–5.5 mmol L?1, standard TB concentration: 1.7–17.1 μmol L?1, standard serum AST level: 13–35 U L?1, and standard serum ALT level: 7–40 U L?1. TB, total bilirubin; AST, aspartate aminotransferase; ALT, alanine aminotransferase; IQR, interquartile range; WT, wide type of FMO3.

VRC Cmin adjusted on VRC dose (VRC Cmin/D) to overcome the influence of VRC dose. After oral administration, the median VRC Cmin/D was 2.23 (103 L?1) in the wide type of FMO3 (WT) group, 2.53 (103 L?1) in the

E158K group, 2.90 (103 L?1) in the E308G group, and 2.49 (103 L?1) in the V257M group. The plasma VRC Cmin/D in the E308G group was significantly higher than that in the WT group (p = 0.0005), as shown in Figure 3.

伏立康唑代谢和不良反应中的FMO3变异

药理学DOI:10.1159 / 000510327

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下载者:奥克兰理工大学156.62.3.11-2020年10月6日4:36:09 AM

0

c

150

p = 0.028

丙氨酸氨基转移酶,IU L–1

血清钾浓度,mmol L–1

世界品牌女包排名 5

p = 0.03 p = 0.04

60

p = 0.04

20 0

特应性皮炎

FMO3基因型对VRC治疗的临床反应的影响与血液生化指标不同,患者抱怨的临床不良反应通常反映在病历中。该研究收集了这165名患者的医疗记录,按照FMO基因型分组,并获得了具有不良反应症状的患者百分比,如图5所示。药理学DOI:10.1159 / 000510327

p = 0.04世界品牌女包排名

40

Influence of FMO3 Genotypes on Serum Parameters Among the patients who took VRC orally, there were 15 patients with hypokalemia, and the distribution of serum potassium levels in each group is shown in Figure 4a. The serum potassium level in the FMO3 E308G genotype group was significantly lower than that in the WT group (p = 0.028). An abnormal increase in TB occurred in 38 patients, and the distribution of blood TB level in each group is shown in Figure 4b. The abnormal increase in the TB level in the FMO3 E308G genotype group was more significant than that in the WT group (p = 0.049). At the same time, the FMO3 E308G genotype group and E158K genotype group were more likely to have an abnormal AST level. As shown in Figure 4c, there were 27 patients with an abnormal increase in the AST level. Compared with the WT group, the AST level in the E308G genotype group increased significantly (p = 0.03) and the AST level in the E158K genotype group increased significantly (p = 0.047). The level of ALT in each group is also shown in Figure 4d. Compared with the FMO3 WT group, E158K, E308G, and V257M genotype groups also had abnormal growth in different degrees, but there were no significant differences.

6

p = 0.03

周围水肿

头痛

腹泻

视力障碍

Atopic dermatitis and visual impairment are common adverse reactions of VRC treatment. In this study, the patients with these adverse reactions were analyzed, in which the incidence of the FMO3 E308G genotype group was 67 and 75%, respectively, compared with the WT genotype group, where the incidence rate was significantly different (p = 0.03). Similarly, the incidences of peripheral edema, headache, and diarrhea in the E308G group were 57, 50, and 60%, respectively, which were significantly different from those in the WT group (p = 0.04). Discussion

In the present study, after the determination of the CYP2C19 metabolic phenotype and FMO3 genotype in all patients, we conducted a statistical analysis mainly on 165 patients with adverse reactions. There was no difference in patients’ age, underlying diseases, genotypes, and average VRC dose between different genders. The metabolic phenotype of CYP2C19 in 165 patients was the same as IM, but there were significant individual differences in FMO3 genotypes. Among these individuals, patients with genotype E308G had a higher risk of adverse reactions than patients with other FMO3 genotypes (WT/E158K/V257M). The FMO3 E308G genotype leads to the increase of plasma VRC Cmin/D. It is suggested that the FMO3 E308G genotype with lower metabolic activity can increase the plasma concentration of VRC, and thus, the FMO3 genotype may play a novel role in altering the adverse reactions of VRC. According to the FDA-approved VRC instructions (Vfend? Tablets; Ascoli Piceno, Italy), there is a wide Wang/Zhao/Wen/Liao/Luo

下载者:奥克兰理工大学156.62.3.11-2020年10月6日4:36:09 AM

图5. FMO3基因型和对VRC治疗的临床反应。在伏立康唑治疗期间,不同基因型患者的主要不良反应发生率以百分比表示。通过χ2检验或Fisher精确检验进行统计分析。重要的p值显示在比较栏上方。 VRC,伏立康唑; WT,FMO3的宽类型。

发生率,%

80

■ WT ■ E158K ■ E308G ■ V257M

彩色版本可在线获得

100

as patients with neutropenia, stem cell transplantation, and other immunodeficient diseases. Therefore, adverse reactions caused by VRC, such as visual adverse events, headache, diarrhea, and liver function [27], are important parameters for individualized treatment of patients with different genotypes. As expected, abnormalities in the liver function test (TB/AST/ALT) are associated with the use of VRC, which is consistent with the results reported in previous studies [28]. The results of the present study showed that the number of patients with an abnormal increase in AST was 26 (15.8%), and the total incidence of clinically significant transaminase abnormalities in patients who participated in the VRC treatment study reported by Pfizer was 12.4%. The data are slightly higher (Pfizer; data on file), which may be due to the small sample size or ethnic reasons in this study. According to the meta-analysis, there is no correlation between CYP2C19 phenotype, hepatotoxicity, and neurotoxicity [29]. There are only few clinical reports about the effect of FMO3 genotype on the incidence of adverse reactions to VRC. This study suggests that FMO3 genotypes in patients with neutropenia may affect the adverse reactions of VRC by changing plasma exposure. According to the results of the present study, it is found that FMO3 genotyping may help patients use VRC more safely. The main advantage of this study is evaluation of the safety of FMO3 genotypes in VRC treatment of FN with the same phenotype of CYP2C19. To our knowledge, this study is the first to report the effect of the FMO3 E308G genotype on the pharmacokinetics and adverse reactions of VRC in patients with FN. However, our study also has some limitations. First, as more and more studies have shown that severe inflammation can also affect VRC trough concentration [16, 30], CRP or IL-6 concentration can also be used as an important influencing factor. In this study, we excluded patients with chronic underlying inflammatory diseases, resulting in an insufficient sample size in patients with significant inflammation after prophylactic and empirical use of VRC, and failed to analyze the correlation between CRP or IL-6 and VRC trough concentration in patients with FN. Second, although we have tried our best to make the sample size sufficient and the research methods rigorous, as a single disease (FN) and single observation control study, the adverse reactions associated with FMO3 gene polymorphism and other diseases are limited. Therefore, our findings need to be validated in other diseases and multicenter clinical cohorts. Although these limitations remain, the present study is paving the way to a better understanding of VRC and adverse reactions in disease states (e.g., FN).

伏立康唑代谢和不良反应中的FMO3变异

药理学DOI:10.1159 / 000510327

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下载者:奥克兰理工大学156.62.3.11-2020年10月6日4:36:09 AM

range of intraindividual/interindividual variations in VRC plasma concentrations in healthy subjects. Previous studies have mainly reported the genetic polymorphism of CYP2C19 enzyme and the effects of nongenetic factors (age, liver disease, and drug interaction) on this variation, but they still do not explain all individual differences [20, 21], especially in unhealthy subjects [22]. Nowadays, more and more researchers focus on the metabolic pathway of VRC and study the polymorphism of the FMO3 gene in order to further find out the reasons for the individual differences in therapy efficacy and safety of VRC in the state of disease [23]. Since FMO3 SNPs may be involved in the nitrogen oxygenation of some amines, including VRC, it is necessary to identify the SNPs in the FMO3 gene of patients with disease and to study the effects of different genotypes on the activity of FMO3 in patients. Some mutations in FMO3 can enhance or weaken its translation ability, and thus increase or decrease the content of FMO3 in the body, make the substrate metabolism of FMO3 abnormal, and affect the efficacy or adverse drug reactions [24]. The study on the relationship between itopride and FMO3 gene polymorphism showed that the combined mutation of FMO3 E158K and E308G could decrease the activity of FMO3, weaken the metabolism of itopride, and significantly increase the blood concentration of itopride [25]. Yamada et al. [26] reported that E158K and E308G mutations in the FMO3 gene can increase the metabolic activity of FMO3, decrease the plasma concentration of VRC, and change the plasma exposure of VRC. The limitation of Yamada et al.’s study [26] is that it aimed at subjects with different phenotypes of CYP2C19. Different phenotypes of CYP2C19 still have a certain impact on the safety of VRC therapy. With the development of precision therapy, the detection of gene polymorphism is widely used in different diseases and drug treatments. Four polymorphisms in exons 4, 6, and 7 of the FM03 gene: c.G472A (p.E158K), c.G769A (p.V257M), and c. A923G (p.E308G), were detected by restriction fragment length polymorphism. Therefore, the method of detecting the FMO3 genotype in this study is the same as that commonly used in molecular clinical diagnosis and can be used as a routine method to predict whether patients will have serious side effects after VRC treatment. Hepatotoxicity and optic neurotoxicity restrict the timely use of antifungal drugs and cause fatal fungal infections to high-risk populations. Adverse drug reactions are an important indicator of preventive treatment; individualized medicine according to patients’ genotypes can not only help avoid adverse drug reactions but also help fight against fungal infections in high-risk groups, such

Conflict of Interest Statement

结论

这是第一个报道FMO3 E308G的突变会降低FMO3酶的活性并削弱VRC的代谢能力的研究,这可能会增加VRC的血药浓度或导致FN的不良反应。

作者声明,他们没有利益冲突要披露。

资金来源本研究由深圳市龙华区科技创新基金项目(No.2017032)和武汉市卫生委员会资助的教学项目研究基金(No.WX18Z30)资助。

致谢作者要感谢刘江宏对本手稿初稿的反馈。作者还要感谢广东医科大学学生在数据收集过程中的共同努力。

伦理声明本研究是根据赫尔辛基宣言的原则进行的,并得到了深圳市龙华区中心医院审查委员会和伦理委员会的批准。所有入组的患者均收到有关研究的科学目的的信息,并且每个患者均签署了知情同意书。

参与研究设计的作者贡献:王和文;进行了实验:王,赵,廖和罗;进行数据分析:王和文;并为手稿的撰写或撰写做出了贡献:王和文。所有作者都修改并批准了该手稿。

参考文献

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of America. Clin Infect Dis. 2008 Feb 1;46(3): 327–60. ? 6 Maertens JA, Girmenia C, Brüggemann RJ, Duarte RF, Kibbler CC, Ljungman P, et al. European guidelines for primary antifungal prophylaxis in adult haematology patients: summary of the updated recommendations from the European conference on infections in leukaemia. J Antimicrob Chemoth. 2018;73(12): 3221–30. ?7 Veringa A, Geling S, Span LF, Vermeulen KM, Zijlstra JG, van der Werf TS, et al. Bioavailability of voriconazole in hospitalised patients. Int J Antimicrob Agents. 2017; 49(2): 243–6. ? 8 Mangal N, Hamadeh IS, Arwood MJ, Cavallari LH, Samant TS, Klinker KP, et al. Optimization of voriconazole therapy for the treatment of invasive fungal infections in adults. Clin Pharmacol Ther. 2018;104(5):957–65. ? 9 Yanni SB, Annaert PP, Augustijns P, Bridges A, Gao Y, Benjamin DK, et al. Role of flavincontaining monooxygenase in oxidative metabolism of voriconazole by human liver microsomes. Drug Metab Dispos. 2008; 36(6): 1119–25. 10 Yanni SB, Annaert PP, Augustijns P, Ibrahim JG, Benjamin DK, Thakker DR. In vitro hepatic metabolism explains higher clearance of voriconazole in children versus adults: role of CYP2C19 and flavin-containing monooxygenase 3. Drug Metab Dispos. 2010;38(1):25– 31.

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王/赵/温/辽/罗

下载者:奥克兰理工大学156.62.3.11-2020年10月6日4:36:09 AM

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伏立康唑代谢和不良反应中的FMO3变异

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药理学DOI:10.1159 / 000510327

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下载者:奥克兰理工大学156.62.3.11-2020年10月6日4:36:09 AM

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研究论文药理学DOI:10.1159 / 000510327 收到:2020年5月28日接受:2020年7月20日在线发布:2020年9月30日 预测性...
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