CYP2A6基因多态性对丙戊酸钠血药浓度的影响

目的探讨细胞色素P4502A6(CYP2A6)基因多态性对丙戊酸钠血药浓度的影响。方法选择单药服用丙戊酸钠的癫患者98例,应用巢式PCR(nested-primerpolymerasechainreaction)方法分析其CYP2A6基因型,分析等位基因CYP2A6*1及CYP2A6*4;同时应用荧光偏振免疫法(FPIA)测定患者丙戊酸钠的血药浓度。结果98例患者中CYP2A6基因型为*1/*1者73例(74·5%),*1/*4者24例(24·5%),*4/*4者1例(1·0%),根据基因型分为A组(CYP2A6*1/*1)和B组(CYP2A6*1/*4或CYP2A6*4/*4)。B组患者丙戊酸钠的标准血药浓度平均值(4·1393±0·2793)较A组(3·3486±0·3919)高,差异有统计学意义(P<0·05)。结论CYP2A6基因多态性影响丙戊酸钠的血药浓度,含有CYP2A6*4等位基因的患者应用丙戊酸钠应较常规降低用量。     

丙戊酸药物浓度与CYP286基因多态性的相关性研究

目的:探讨丙戊酸(VPA)药物浓度与细胞色素P4502B6(CYP2B6)基因多态性的关系。方法:选择符合入选条件的癫患者72例,提取外周血DNA,应用聚合酶链反应和限制性核酸内切酶方法分析患者的CYP2B6基因型及等位基因;应用荧光偏振免疫法测定患者VPA的血药浓度。结果:72例癫患者中CYP2B6基因型为*1/*1为39例(54.2%),*1/*6为29例(40.3%),*6/*6为4例(5.5%),根据基因型将患者分为两组,A组(CYP2B6*1/*1)和B组(CYP2B6*1/*6或CYP2B6*6/*6)。B组患者VPA的标准血药浓度平均值较A组高,且差异有统计学意义(P<0.05)。结论:CYP2B6是VPA的代谢酶,CYP2B6基因多态性可影响VPA的血药浓度,对含有CYP2B6*6等位基因的患者应用VPA时,其血药浓度高,提示对VPA药物代谢有影响。     

丙戊酸代谢相关CYP2C19基因多态性在癫痫患儿体内的分布及治疗个体化研究

目的：对癫痫患儿体内CYP2C19的基因多态性进行研究,并进行基因型与患儿体内丙戊酸血药浓度关系的研究,以对患儿进行治疗个体化。方法采用聚合酶链反应－限制性片段长度多态性检测技术对2012‐12—2014‐03来我院及其他医院神经内科654例确诊为癫痫患儿的CYP2C19基因型进行检测,同时对仅服用丙戊酸进行抗癫痫治疗的228例患儿体内的丙戊酸稳态血药浓度进行检测,进而探求CYP2C19的基因型与血药浓度的相关性。结果 CYP2C19具有基因多态性,各基因型分布频率不同,其中*1／*1型为41.9％、*1／*2型为41.1％、*1／*3型为6.4％、*2／*2型为7.4％、*2／*3型为2.9％和*3／*3型为0.3％;同时入选组的228例患儿中快、中、慢代谢型所占的频率分别为40.8％、44.7％和13.5％;同时测得*1／*1型、*1／*2型、*1／*3型、*2／*2型、*2／*3型所对应的稳态血药浓度（m g／L ）分别为45±20、64±16、68±21、73±28、72±18;经统计分析发现,*2／*2型与*1／*1型血药浓度体质量剂量比值存在差异具有统计学意义（ P＜0.05）。结论癫痫患儿体内CYP2C19具有多态性,其分布规律与其他正常人群的分布规律基本一致,患儿服用丙戊酸时,其CYP2C19基因型与体内丙戊酸的血药浓度具有相关性。因此提醒我们,对癫痫患儿应用丙戊酸进行抗癫痫治疗时,可参考CYP2C19基因分型结果,预测血药浓度变化,对患儿进行个体化的治疗。     

回、汉族癫痫患者CYP2C9和CYP2C19基因多态性与苯巴比妥血药浓度的相关性研究

目的研究CYP2C9*3和CYP2C19*2的单核苷酸多态性在回、汉族癫痫人群中的分布特点;探讨两种基因型与苯巴比妥血药浓度的关系。方法对宁夏地区回、汉族癫痫患者185例采用聚合酶链反应-限制性片段长度多态性技术(PCR-RFLP)分析CYP2C9*3和CYP2C19*2基因型,并进行回、汉族间基因型及等位基因频率的比较;应用反相高效液相色谱法(RP-HPLC)测定其中113例单用苯巴比妥患者的血药浓度,再将其标准化后,分析两种基因型与苯巴比妥血药浓度的关系。结果 (1)回、汉族癫痫患者中CYP2C9*3和CYP2C19*2基因型及等位基因频率均无统计学差异(P>0.05)。(2)根据所携带的CYP2C9和CYP2C19突变等位基因的数量,将113例单用苯巴比妥的患者分为强代谢(EM)组、中间代谢(IM)组和弱代谢(PM)组,IM组和PM组苯巴比妥血药浓度明显高于EM组,且突变基因携带数量与血药浓度呈正相关。结论苯巴比妥血药浓度在CYP2C9和CYP2C19变异基因携带者中增高,根据患者CYP2C9和CYP2C19基因型可以预测患者药物浓度,指导临床选择合适的苯巴比妥初始剂量。     

河南地区汉族人群丙戊酸钠代谢相关基因CYP2C19的多态性分布调查分析

目的探讨河南地区丙戊酸钠代谢相关基因CYP2C19多态性的相关分布。方法采用聚合酶链反应-限制性片段长度多态性检测技术对我院无亲缘关系的250例患者的基因型进行检测。结果 CYP2C19*1*1频率为46.0%、CYP2C19*1*2频率为38.4%、CYP2C19*1*3频率为6.0%、CYP2C19*2*2频率为6.4%、CYP2C19*2*3频率为2.8%、CYP2C19*3*3频率为0.4%。结论河南地区汉族人群CYP2C19多态性的相关分布与全国其他地区比较无显著性差异,临床医师在使用丙戊酸钠及苯妥英钠等药物进行抗癫治疗时可以参考相关基因检测结果。     

癫痫患儿丙戊酸钠血药浓度监测

目的监测癫痫儿童血浆丙戊酸钠浓度,以供临床参考。方法采用均相酶放大免疫法测定413例癫痫儿童丙戊酸钠血药浓度,并对结果进行分析。结果共检测413例癫痫儿童丙戊酸钠血浆药物浓度,低于有效浓度(50mg/L)组125例(30.3%),达到有效浓度(50~100mg/L)组268例(64.9%),高于有效浓度(100mg/L)组20例(4.8%),3岁年龄组丙戊酸钠血药浓度(52.16±22.35)mg/L较3~6岁年龄组(61.45±22.11)mg/L、6岁年龄组(63.40±23.83)mg/L血药浓度降低,差异具有统计学意义(P0.05)。结论丙戊酸钠血药浓度检测结果具有个体差异性,不同年龄组用药剂量应适当调整。检测丙戊酸血药浓度有助于个体化用药,指导增加疗效、控制不良反应。     

丙戊酸钠、托吡酯诱导癫癎患者体重及血清瘦素水平的变化

目的观察丙戊酸钠、托吡酯诱导癫癎患者体重及血清瘦素水平的变化。方法40例女性癫癎患者按年龄、体重指数分层匹配进入丙戊酸钠、托吡酯治疗组,每组20例。在治疗前及治疗3个月后分别测定身高、体重及早晨空腹血清瘦素水平。结果9例经丙戊酸钠治疗者体重增加(≥4kg),血清瘦素水平[(13.2±3.6)ng/ml]高于治疗前[(7.4±3.0)ng/ml,P<0.01];6例托吡酯治疗者体重减轻(≥4kg),血清瘦素水平[(3.7±1.8)ng/ml]低于治疗前[(7.4±2.6)ng/ml,P<0·01]。结论经丙戊酸钠治疗体重增加者出现瘦素抵抗,经托吡酯治疗体重减轻者血清瘦素水平降低。     

CYP2C19基因型对丙戊酸及其与苯妥英联合用药时血药浓度影响

目的探讨细胞色素P450 2C19(CYP2C19)基因对丙戊酸(VPA)血药浓度,以及VPA和苯妥英(PHT)联合应用时对其VPA血药浓度的影响.方法应用变性高效液相(DHPLC)技术对CYP2C19两个常见的等位基因突变进行了分析;应用荧光偏振免疫法(FPIA)测定口服抗癫痫药物患者的血药浓度.结果81例癫痫患者中CYP2C19外显子4(*3)和外显子5(*2)位点均为野生型(*1/*1)的发生率为37.0%,CYP2C19*2和CYP2C19*3的等位基因频率分别为31.5%和3.7%.单一应用VPA时,弱代谢患者较正常代谢患者的VPA血药浓度有所升高(P＜0.05).联合应用PHT和VPA可使VPA血药浓度显著降低(P＜0.01),CYP2C19正常代谢患者VPA血药浓度降低尤为明显(P＜0.01);在VPA与PHT联合用药过程中,约半数CYP2C19正常代谢患者VPA血药浓度不能达到治疗血药浓度.结论CYP2C19基因多态性影响VPA的血药浓度变化,在联合应用PHT时对VPA血药浓度的影响尤为明显,从而影响抗癫痫的临床疗效.     

不同剂型丙戊酸钠治疗儿童癫血药浓度监测及临床分析

目的探讨癫患儿使用不同剂型丙戊酸钠制剂对血药浓度的影响及临床疗效。方法采用高效液相色谱法对582例服用不同剂型丙戊酸钠患儿进行血药浓度测定,分为丙戊酸钠缓释片组261例,丙戊酸钠口服片组223例,丙戊酸钠普通片剂组98例,对3组监测结果及临床疗效对比分析。结果丙戊酸钠缓释片组血药浓度谷水平为(72.56±18.62)mg/L,口服液组为(50.23±21.88)mg/L,普通片剂组为(41.43±19.87)mg/L。缓释片组血药谷浓度最高,普通片剂组最低,3组相比差异有统计学意义(P<0.05);缓释片组与口服液组临床疗效比较差异无统计学意义(P>0.05),与普通片剂组比较差异有统计学意义(P<0.05)。结论服用丙戊酸钠缓释剂血药谷浓度相对较高,且依从性好,值得临床推广。     

神经外科术后早期癫痫的治疗及病因研究

目的探讨神经外科围手术期常规应用丙戊酸钠进行预防后仍出现术后早期癫痫的治疗方法及病因。方法对幕上开颅患者在术前、术中和术后应用丙戊酸钠进行癫痫预防。对预防后出现术后早期癫痫者立刻给予丙戊酸钠(15mg/kg)静脉注射,同时增加丙戊酸钠静脉维持剂量[1.5mg/(kg·h)],观察20min,无效者再次给予丙戊酸钠(18mg/kg)静脉注射。观察其疗效及副作用,并分析术后早期癫痫与疾病、手术损伤、颅内出血及抗癫痫药物血药浓度等关系。结果全组29例病人,丙戊酸钠治疗有效23例(79%),30min内控制癫痫发作,无复发;无效用其他药物6例(21%),测得最高丙戊酸钠血药浓度为150mg/L,无明显副作用。全组病例中20名患者在癫痫发生后首次丙戊酸钠静注(15mg/kg)后10min,所测丙戊酸钠血浓度低于70mg/L,全部应用丙戊酸钠针剂控制癫痫者血药浓度大于80mg/L。同时分析此29例病人,发现术后早期癫痫65%发生在术后6h内,平均手术时间为5.2h。72%早期癫痫患者为右侧额叶病变,72.4%早期癫痫患者在术中有侧裂静脉及额叶回流至矢状窦静脉损伤,31%术后早期癫痫患者术后复查头颅CT有蛛网膜下腔出血(SAH)或脑内血肿。结论丙戊酸钠在治疗术后早期癫痫中效果肯定,无明显副作用。预防后仍出现术后早期癫痫与疾病部位、术中静脉损伤、术后颅内出血、脑水肿、手术时间及丙戊酸钠血药浓度偏低有关。     

The influence of cytochrome oxidase CYP2A6, CYP2B6, and CYP2C9 polymorphisms on the plasma concentrations of valproic acid in epileptic patients

Objectives

To investigate influences of the functional polymorphisms of Cytochrome P450 isozymes 2A6 (CYP2A6), 2B6 (CYP2B6), and 2C9 (CYP2C9) on pharmacokinetics of VPA in vivo.

Patients and methods

In the study, we analyzed the genotypes of CYP2A6, CYP2B6, and CYP2C9 and their contribution to the steady-state standardized plasma VPA concentrations in 179 subjects with epilepsy of a Northern Han Chinese population. The genotypes were detected by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP).

Results

The subjects with one or two variant CYP2A6*4 alleles showed higher mean plasma VPA concentrations compared with non-*4 alleles [(3.4 ± 0.4) μg kg ml⁻¹ mg⁻¹ vs. (3.6 ± 0.4) μg kg ml⁻¹ mg⁻¹, p = 0.0055]. A significant difference [one-way ANOVA (p = 0.0203)] was also found between mean plasma VPA concentrations and the CYP2B6 genotypes. In addition, subjects with the heterozygous genotype CYP2C9*3 had higher mean plasma VPA concentrations than did those subjects with the wild-type genotype [(3.9 ± 0.4) μg kg ml⁻¹ mg⁻¹ vs. (3.4 ± 0.4) μg kg ml⁻¹ mg⁻¹, p = 0.0001].

Conclusion

The presently evaluated variant alleles in the CYP2A6, CYP2B6, and CYP2C9 genes may explain part of the substantial variability in VPA pharmacokinetics between different subjects.     

The impact of the CYP2D6-polymorphism on dose recommendations for current antidepressants

Cytochrome P450 CYP2D6 represents an extensively characterized polymorphic drug-metabolizing enzyme. The CYP2D6-gene is highly polymorphic and more than 70 different alleles are known currently. The activity of the enzyme markedly varies among individuals from poor to intermediate and extensive up to ultrarapid metabolism on the basis of the polymorphism of the CYP2D6 gene. Association studies provide growing evidence for the clinical importance of the CYP2D6 polymorphism investigating whether the CYP2D6 genotype distribution differs from that of the normal population either in patients with marked adverse effects or in nonresponders during treatment with CYP2D6 substrates. However, these scientifically important studies present less information for dose adjustments necessary to individualize pharmacotherapy in a given clinical case. With respect to psychopharmacological drug metabolism several antidepressants were characterized as being CYP2D6 substrates. Thus, this review summarizes dose recommendations of current antidepressants.     

Utility and adoption of CYP2D6 and CYP2C19 genotyping and its translation into psychiatric clinical practice

Jürgens G, Jacobsen CB, Rasmussen HB, Werge T, Nordentoft M, Andersen SE. Utility and adoption of CYP2D6 and CYP2C19 genotyping and its translation into psychiatric clinical practice. Objective: To describe clinical utility and adoption of routinely offered CYP2D6 and CYP2C19 genotyping (CYP test) in daily clinical practice of a psychiatric centre. Method: We described psychiatrists translations of CYP test results in patients with genotypes indicating poor or ultrarapid metabolizer status and treated with at least one CYP‐dependent drug based on a retrospective review of medical records. Complementary, we used ethnographic participant observation and qualitative interviews to identify the barriers and incentives for the use of CYP test results. Results: The cohort study included 101 of 1932 cases genotyped between 2003 and 2009. In 53 of 101 cases, test results were addressed in medical records. The most frequent response was to monitor drug concentrations (23 cases), observe for adverse events (18 cases) and adjust dosage (13 cases). In 33 of 101 cases, results were mentioned in the discharge letter. The ethnographic study indicated a poor adoption of the CYP test in clinical praxis. Test results were lost in workflows and knowledge transfer between laboratory and clinician and were absent from clinical routines, treatment conferences and educational fora. Conclusion: The CYP test has not gained foothold in clinical practice, and its potential clinical benefits are not utilized.     

CYP2B6 genotype alters abstinence rates in a bupropion smoking cessation trial.

BACKGROUND: CYP2B6 is the primary enzyme involved in bupropion (Zyban; GlaxoSmithKline, Research Triangle Park, North Carolina) metabolism. Genetic polymorphisms in CYP2B6, such as CYP2B6*6, can alter bupropion metabolism and may affect bupropion treatment outcome. METHODS: Subjects participated in a smoking cessation clinical trial of bupropion versus placebo. The main outcome was a 7-day point prevalence abstinence rate measured 10 weeks after the start of treatment (i.e., end of treatment) and at the 6-month follow-up; secondary outcomes were severity of adverse effects, withdrawal, and urge to smoke. Subjects were haplotyped for the CYP2B6*6 variants. RESULTS: Among smokers in the CYP2B6*6 group (CYP2B6*1/*6 or CYP2B6*6/*6 genotype, n = 147, 45% of the population), bupropion produced significantly higher abstinence rates than placebo at the end of treatment (32.5% vs. 14.3%, p = .01) and at the 6-month follow-up (31.2% vs. 12.9%, p = .008). In contrast, bupropion was no more effective than placebo for smokers in the CYP2B6*1 group (CYP2B6*1/*1, n = 179) at the end of treatment (31.0% vs. 31.6%, p = .93) or at the 6-month follow-up (22.0% vs. 21.5%, p = .94). There was a significant genotype by treatment interaction at the end of treatment (odds ratio [OR] = 2.97, confidence interval [CI] = 1.05-8.40, p = .04), which was similar at 6-month follow-up (OR = 2.98, CI = .98-9.06, p = .05). CONCLUSIONS: These data suggest that smokers with the CYP2B6*6 genotype have a higher liability to relapse on placebo and that they may be good candidates for bupropion treatment for smoking cessation.     

No evidence of an association between CYP2D6 polymorphisms among Japanese and dementia with Lewy bodies

Dementia with Lewy bodies (DLB) is the second most frequent degenerative dementia among the elderly, following Alzheimer-type dementia (ATD). An association of DLB with CYP2D6*4, one of the cytochrome P450IID6 (debrisoquine 4-hydroxylase; CYP2D6) gene polymorphisms, was reported previously, but this is controversial. Moreover, these reports have been restricted to Caucasian populations. Therefore, we compared frequencies of CYP2D6*3, *4, and *10 mutant alleles in 17 Japanese DLB patients to those among Alzheimer-type dementia (ATD) patients and healthy controls. Polymerase chain reaction amplification and restriction fragment length polymorphism analyses were used for genotyping. No significant difference of genotype or mutant allele frequencies was detected between DLB, ATD, and healthy controls. The present results do not support the suggestion that the CYP2D6 gene is related to DLB susceptibility, at least in the Japanese population.     

CYP2D6 P34S Polymorphism and Outcomes of Escitalopram Treatment in Koreans with Major Depression

Objective

Cytochrome P450 (CYP) enzymatic activity, which is influenced by CYP genetic polymorphism, is known to affect the inter-individual variation in the efficacy and tolerability of antidepressants in major depressive disorder (MDD). Escitalopram is metabolized by CYP2D6, and recent studies have reported a correlation between clinical outcomes and CYP2D6 genetic polymorphism. The purpose of this study was to determine the relationship between the CYP2D6 P34S polymorphism (C188T, rs1065852) and the efficacy of escitalopram treatment in Korean patients with MDD.

Methods

A total of 94 patients diagnosed with MDD were recruited for the study and their symptoms were evaluated using the 21-item Hamilton Depression Rating scale (HAMD-21). The association between the CYP2D6 P34S polymorphism and the clinical outcomes (remission and response) was investigated after 1, 2, 4, 8, and 12 weeks of escitalopram treatment using multiple logistic regression analysis and χ² test.

Results

The proportion of P allele carriers (PP, PS) in remission status was greater than that of S allele homozygotes (SS) after 8 and 12 weeks of escitalopram treatment. Similarly, P allele carriers exhibited a greater treatment response after 8 and 12 weeks of escitalopram treatment than S allele homozygotes.

Conclusion

Our results suggest that the P allele of the CYP2D6 P34S polymorphism is a favorable factor in escitalopram treatment for MDD, and that the CYP2D6 P34S polymorphism may be a good genetic marker for predicting escitalopram treatment outcomes.     

Analysis of Lithuanian CYP2D6 polymorphism and its relevance to psychiatric care of the local population

Background: CYP450 system gene CYP2D6 polymorphisms have been associated with an altered response to psychotropic drugs. While there exists interindividual and interethnic differences of clinical significance, there is no data concerning the Lithuanian population.

Aims: To determine the distribution of CYP2D6 alleles and predicted phenotype in the Lithuanian population, compare it to other Europeans and find the differences between patients with affective disorders and the healthy population.

Methods: Our study sample consisted of 179 subjects that included 104 healthy volunteers and 75 patients with clinical diagnosis of affective disorders according to ICD-10AM classification, treated in hospital settings. DNA samples were taken from the blood and alleles of the CYP2D6 gene were determined for each participant. Frequencies were compared to other Europeans.

Results: The frequency of the most common alleles *1 and *2 was 45.0% and 28.8% accordingly. Dysfunctional *5 (1 vs. 30, p?<?.002) allele was less frequent in Lithuania inhabitants than previously established in other Europeans. There were no polymorphisms of the CYP2D6 gene that could be associated with changes in drug metabolism in the patients. The functional CYP2D6 *2 allele was more prevalent in the control group, while the non functional CYP2D6 *4 allele was more prevalent in the patient group (p?<?.05 for both cases).

Conclusion: The genetic makeup of Lithuanians was generally comparable to other Europeans, but fewer Lithuanians had non-functional *5 allele. More patients had non-functional alleles. Study findings contradict previous results from other countries, where CYP2D6 gene polymorphism was associated with treatment outcomes.     

CYP2D6 gene deletion allele in patients with neuroleptic malignant syndrome: preliminary report

Neuroleptic malignant syndrome (NMS) is a potentially fatal adverse reaction to psychopharmacologic treatment. Reported herein are two NMS patients with schizophrenia who were found to possess a CYP2D6 gene deletion allele (CYP2D6*5). The deletion results in decreased CYP2D6 activity, possibly leading to drug accumulation. Both patients with NMS had been treated with neuroleptics, including CYP2D6 substrates. Polymerase chain reaction (PCR) followed by restriction fragment length polymorphism analyses and long PCR were performed to detect CYP2D6 genotype. One patient was found to possess *5/*10; the other had a *1/*5 genotype. The present preliminary report suggests that pharmacokinetic factors cannot be excluded and the CYP2D6 polymorphism is possibly associated with the etiology of NMS.