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。     

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.     

细胞色素P450等位基因多态性与丙戊酸钠血药浓度的相关性

目的探讨细胞色素P450(CYP)2A6及CYP2B6等位基因多态性与丙戊酸钠血药浓度的关系。方法选择165例服用丙戊酸钠单药治疗且无肝肾功能异常的癫疒间患者,应用多聚酶链反应(PCR)方法分别进行CYP2A6(95例)和CYP2B6(70例)等位基因多态性频率分析;应用荧光偏振免疫法(FPIA)测定含不同等位基因患者丙戊酸钠的血药浓度。结果95例患者中,CYP 2A6*4等位基因频率为13.2%,CYP2A6*4等位基因携带者丙戊酸钠的血药浓度[(4.23±0.27)mg/ml]明显高于非CYP2A6*4等位基因携带者[(3.35±0.38)mg/ml](P<0.05);70例患者中,CYP2B6*6等位基因频率为24.3%,CYP2B6*6等位基因携带者丙戊酸钠的血药浓度[(4.12±0.34)mg/ml]明显高于非CYP2B6*6等位基因携带者[(3.07±0.28)mg/ml](P<0.05)。结论CYP2A6或(和)CYP2B6等位基因多态性均影响丙戊酸钠的血药浓度,CYP2A6*4或(和)CYP2B6*6等位基因携带者丙戊酸钠用量应低于常规剂量,以减少不良反应的发生和避免药物资源的浪费。     

CYP2C19基因多态性对长期服用氯吡格雷脑梗死患者卒中复发的影响

目的探讨长期服用氯吡格雷的初发脑梗死患者卒中复发与CYP2C19基因多态性的关系。方法对78例初发脑梗死后长期(≥1 y)服用氯吡格雷的患者,根据入组时是否脑梗死复发分为复发组与未复发组,通过CYP2C19基因芯片检测系统对两组患者的CYP2C19基因型进行检测。结果 78例中,复发组32例,未复发组46例。两组患者在性别、年龄、吸烟、高血压、糖尿病、血脂等的差异均无统计学意义(均P>0.05);所检的78例共检出三种等位基因:CYP2C19*1、CYP2C19*2、CYP2C19*3,等位基因频率分别是61.54%、33.33%、5.13%。两组患者共检出6种基因型:CYP2C19*1/*1、CYP2C19*1/*2、CYP2C19*1/*3、CYP2C19*2/*2、CYP2C19*2/*3和CYP2C19*3/*3。未复发组CYP2C19*1等位基因和CYP2C19*1/*1基因型频率显著高于复发组,分别为76.1%:40.6%(P<0.01),58.7%:18.8%(P<0.001),而未复发组CYP2C19*2等位基因频率和CYP2C19*2/*2基因型频率显著低于复发组,分别为19.6%:53.1%(P<0.01),4.3%:31.3%(P<0.01),而两组其余等位基因频率和基因型频率差异无统计学意义(均P>0.05)。结论长期服用氯吡格雷的脑梗死患者卒中复发与CYP2C19基因突变有关,对于需长期服用氯吡格雷预防脑梗死复发的患者,进行CYP2C19基因型的检测是必要的。     

CYP2C19基因多态性与奥氮平所致药物性肝损伤的关联性研究

目的:研究细胞色素酶CYP2C19基因多态性与奥氮平所致药物性肝损伤(DILI)间的关联性。方法:对127例单一服用奥氮平的精神分裂症患者的CYP2C19位点rs4244285、rs4986893、rs12248560进行基因分型检测,分析比较服药后出现药物性肝损伤(DILI)患者(DILI组)与未出现DILI患者(非DILI组)3个SNPs等位基因及基因型频率差异。结果:两组间3个等位基因和基因型频率、各代谢类型频率比较差异无统计学意义(P0.05),在3位点基因类型比较中,DILI组*1/*3基因频率低于非DILI组,差异有统计学意义(P=0.034)。结论:CYP2C19基因多态性与奥氮平所致DILI易感性可能有关,CYP2C19中*1/*3基因型可能是奥氮平所致DILI的保护性因素。     

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。     

CYP2C19基因多态性与急性脑梗死患者氯吡格雷疗效的相关性研究

目的探讨急性脑梗死患者CYP2C19基因多态性与氯吡格雷疗效的相关性。方法采用限制性片段长度多态性PCR法对171例急性脑梗死患者进行CYP2C19基因多态性检测。所有患者给予氯吡格雷治疗2周。分别于治疗前及治疗后第1 d、第5 d进行血小板聚集率检测,于治疗前及治疗后第1周、第2周进行NIHSS和日常生活活动能力评价(ADL)评分。计算血小板聚集抑制率并进行分析。结果本组171例患者中野生型纯合子(A组)79例,均为CYP2C19*1/*1;野生型基因与突变基因杂合子(B组)71例,包括55例CYP2C19*1/*2及16例CYP2C19*1/*3;突变基因纯合子或杂合子(C组)21例,包括11例CYP2C19*2/*2、9例CYP2C19*3/*3及1例CYP2C19*2/*3。治疗后第1 d及第5 d时,3组间血小板聚集抑制率的比较差异均有统计学意义(均P0.05)。与治疗前比较,3组治疗后第1周、第2周NIHSS评分均显著降低,ADL评分均显著升高(均P0.05)。与A组比较,B组及C组治疗后第1周、第2周NIHSS评分均明显升高,ADL评分均明显降低(均P0.05)。多因素Logistic回归分析显示,吸烟(OR=1.584,95%CI:1.079~2.136,P=0.004)及CYP2C19基因多态性(OR=1.837,95%CI:1.106~2.540,P=0.002)均与急性脑梗死患者血小板聚集抑制率独立相关。结论 CYP2C19基因多态性可影响急性脑梗死患者氯吡格雷治疗的疗效。     

CBZ和CBZE血药浓度个体差异与CYP3A5*3基因多态性的相关性分析

目的 探讨卡马西平(CBZ)药物代谢个体差异性的遗传学机制,从而指导临床抗癫痫治疗中的个体化用药.方法 选取确诊为癫痫并适用CBZ的患者58例.首先利用PCR技术扩增患者外周血中包含等位基因CYP3A5*3(rs776746)的基冈片段;其次采用基因测序法确定该等位基因各基因型的分布,将包含原始碱基(A)的基因序列归为A组,而将只含有突变碱基(C)的基因序列归为B组;最后,应用高效液相色谱法测定两组患者外周血中CBZ及其代谢产物10,11-环氧化卡马西平(CBZE)的血药浓度.采用t检验,比较A、B两组患者CBZ和CBZE血药浓度的差异.结果 A组患者CBZ的浓度明显低于B组(P＜0.01);A组患者CBZE的浓度明显高于B组(P＜0.05).CYP3A5 * 3的基因多态性与CBZ及其代谢产物CBZE的血药浓度相关,CYP3A5*3突变纯合型CBZ代谢减慢,血药浓度相应增高,应给予相对小剂量的CBZ,以提高临床用药的安全性.结论 CYP3A5*3的基因多态性可能作为临床治疗中CBZ剂量个体化的一项重要参考依据.     

CYP3A5基因多态性与肾移植后钙调神经蛋白抑制剂慢性肾毒性的相关性

背景：钙调神经蛋白抑制剂是实体器官移植后抗排斥治疗中最重要的一线药物之一，主要通过包括CYP3A5在内的CYP3A亚家族进行代谢。但关于CYP3A5基因多态性与钙调神经蛋白抑制剂慢性肾毒性的相关研究国内外鲜有报道。 目的：观察CYP3A5基因多态性与中国人群中钙调磷酸酶抑制剂慢性肾毒性发生的关系。 方法：分别收集200例肾移植后出现慢性肾毒性的中国人种患者设为肾毒组；200例肾移植至少12个月后没有出现慢性肾毒性的中国人种患者设为对照组，取两组血样和临床数据。采用聚合酶链反应-限制性内切酶片段长度多态性技术分别检测两组的CYP3A5突变位点基因型。通过统计学分析CYP3A5的基因多态性与钙调神经蛋白抑制剂慢性肾毒性之间的关系。 结果与结论：慢性肾毒组中CYP3A5基因型*1/*1+*1/*3(显示CYP3A5活性)和*3/*3(不显示CYP3A5活性)分别占39.5%(79/200)和60.5%(121/200)；对照组中CYP3A5基因型*1/*1+*1/*3(显示CYP3A5活性)和*3/*3(不显示CYP3A5活性)分别占28.5%(57/200)和71.5%(143/200)。两组间差异有显著性意义(χ2=9.000，P < 0.05，OR=1.638，95%CI=1.078-2.488)。通过Logistic回归分析CYP3A5*1/*1和CYP3A5*1/*3是显著的引起CNI慢性肾毒性的危险因素(P < 0.05，OR=1.638，95%CI=1.078~2.488)。提示，CYP3A5的基因多态性可能增加肾移植患者慢性肾毒性的遗传易感性；参与钙调神经蛋白抑制剂慢性肾毒性疾病的发生。     

急性脑梗死患者基因多态性对氯吡格雷疗效及终点事件的影响

目的探讨急性脑梗死患者基因多态性对氯吡格雷疗效及终点事件的影响。方法选取2016-06—2017-06新乡市第一人民医院神经内科收治的急性脑梗死患者418例。口服氯吡格雷5 d后抽取外周肘静脉血,血栓弹力图仪测定血小板抑制率。采用改良多重高温连接酶检测反应技术(iMLDR)对患者CYP2C19与ABCBl基因多态性进行分型。出院后进行24个月的随访,记录主要终点事件发生类别及时间。结果根据CYP2C19*2/*3快速代谢型、中间代谢型、慢代谢型的血小板抑制率之间,以及ABCBl C3435T不同基因型之间差异均有统计学意义(P0.01);而ABCBlT(-620)C不同基因型的血小板抑制率之间差异无统计学意义(P0.05)。校正可能的混杂因素后,进行多元线性回归分析显示,CYP2C19*2/*3、ABCBl C3435T是血小板抑制率的独立影响因素;同时还发现体重指数(BMI)26 kg/m~2也是血小板抑制率的独立影响因素。共382例患者完成随访研究,终点事件发生率为13.61%(52/382),其中缺血性脑卒中复发36例(9.42%),心肌梗死4例(1.05%),血管性死亡12例(3.14%)。根据是否携带CYP2C19*2/*3基因分为2组,生存分析Log-Rank检验显示差异有统计意义(P0.05);而ABCBlT(-620)C、ABCBl C3435T基因的显性与阴性患者生存曲线间差异无统计学意义(P0.05)。多因素Cox回归分析显示,CYP2C19*2/*3基因携带是临床终点时间的独立危险因素;同时年龄也是临床终点时间的独立危险因素。结论携带CYP2C19*2/*3、ABCBl C3435T等位基因的急性脑梗死患者氯吡格雷疗效降低,其中携带CYP2C19*2/*3等位基因的患者终点事件风险增高。     

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.     

Pharmacogenetic aspects of therapy with cholinesterase inhibitors: the role of CYP2D6 in Alzheimer's disease pharmacogenetics

Recent studies demonstrate that the therapeutic response in Alzheimer's disease (AD) is genotype-specific. More than 200 genes are potentially associated with AD pathogenesis and neurodegeneration, and approximately 1,400 genes distributed across the human genome account for 20 to 95% of variability in drug disposition and pharmacodynamics. Cytochrome P450 enzymes encoded by genes of the CYP superfamily, such as CYP1A1 (15q22-q24), CYP2A6 (19q13.2), CYP2C8 (10q24), CYP2C9 (10q24), CYP2C19 (10q24.1-q24.3), CYP2D6 (22q13.1), CYP2E1 (10q24.3-qter), and CYP3A5 (7q22.1), acting as terminal oxidases in multicomponent electron transfer chains which are called P450-containing monooxygenase systems, metabolize more than 90% of drugs. Some of the enzymatic products of the CYP gene superfamily can share substrates, inhibitors and inducers whereas others are quite specific for their substrates and interacting drugs. Some cholinesterase inhibitors (tacrine, donepezil, galantamine) are metabolized via CYP-related enzymes, especially CYP2D6, CYP3A4, and CYP1A2. The distribution of CYP2D6 genotypes in the Spanish population is the following: (a) Extensive Metabolizers (EM)(51.61%): *1/*1, 47.10%; and *1/*10, 4.52%; (b) Intermediate Metabolizers (IM)(32.26%): *1/*3, 1.95%; *1/*4, 17.42%; *1/*5, 3.87%; *1/*6, 2.58%; *1/*7, 0.75%; *10/*10, 1.30%; *4/*10, 3.23%; *6/*10, 0.65%; and *7/*10, 0.65%; (b) Poor Metabolizers (PM)(9.03%): *4/*4, 8.37%; and *5/*5, 0.65%; and (c) Ultrarapid Metabolizers (UM)(7.10%): *1xN/*1, 4.52%; *1xN/*4, 1.95%; and CYP2D6 gene duplications, 0.65%. PMs and UMs also accumulate genotypes of risk associated with APOE-, PS-, ACE-, and PRNP-related genes. Approximately, 15% of the AD population may exhibit an abnormal metabolism of cholinesterase inhibitors; about 50% of this population cluster would show an ultrarapid metabolism, requiring higher doses of cholinesterase inhibitors to reach a therapeutic threshold, whereas the other 50% of the cluster would exhibit a poor metabolism, displaying potential adverse events at low doses. In AD patients treated with a multifactorial therapy, including cholinesterase inhibitors (e.g., donepezil), the best responders are the CYP2D6-related EMs and IMs, and the worst responders are PMs and UMs. In addition, the presence of the APOE-4 allele in genetic clusters integrating CYP2D6 and APOE genotypes contributes to deteriorate the therapeutic outcome. From these data, it can be postulated that pharmacogenetic and pharmacogenomic factors are responsible for 75-85% of the therapeutic response in AD patients treated with conventional drugs.     

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 effect of cytochrome P450 2D6 genotypes on haloperidol metabolism: a preliminary study in a psychiatric population

We investigated the effect of cytochrome P450 (CYP2D6) genotypes on plasma levels of haloperidol (HAL) and reduced haloperidol (RHAL) in 47 Japanese male schizophrenic inpatients being treated with HAL. Mutation-specific polymerase chain reaction (PCR) analysis was used to detect CYP2D6*10 as the C188C1T mutation in exon 1. A long-PCR analysis method was used to detect CYP2D6*5. Allele frequencies of CYP2D6*5 and CYP2D6*10 were 4.3% and 34.0%, respectively. Plasma concentrations of HAL and RHAL were measured using high-performance liquid chromatography. The ranges of the plasma concentration of HAL and RHAL corrected to the dose were 0.28-1.60 (mean +/- SD, 0.66+/-0.25, n = 47) ng/mL/mg and 0.03-3.00 (mean+/-SD, 0.36+/-0.46, n = 47) ng/mL, respectively. Plasma RHAL/HAL ratios (R/H ratios) ranged from 0.06 to 1.88 (mean +/- SD, 0.48+/-0.32, n = 47). The analysis was performed among the four genotype groups: CYP2D6*1/CYP2D6*1 (n = 11), CYP2D6*1/CYP2D6*10 (n = 11), CYP2D6*10/CYP2D6*10 (n = 6) and those who have CYP2D6*5 allele (CYP2D6*1/ CYP2D6*5 or CYP2D6*5/CYP2D6*10 (n = 4). We observed significant tendency in effects of CYP2D6 genotypes on plasma concentration of HAL and significant effects on plasma concentration of RHAL, and R/H ratio. These results we obtained suggested that the plasma concentration of HAL and RHAL were determined partly by CYP2D6 polymorphic activity.     

The genetic factors affecting drinking behaviors of korean young adults with variant aldehyde dehydrogenase 2 genotype

Objective

We determined whether aldehyde dehydrogenase 2 (ALDH2) activity alters the way in which drinking behaviors are affected by gene polymorphisms of other alcohol-metabolizing enzymes and serotonin-related proteins.

Methods

Through a follow-up survey with a cohort comprising 551 university freshmen over a period of 6 years, we examined the genetic factors affecting drinking behaviors. In 2000, drinking behaviors were assessed and tryptophan hydroxylase (TPH) and ALDH2 gene polymorphisms were determined. Drinking behaviors were repeated in 2006 (n=150), and the gene polymorphisms of ADH1B, ADH1C, CYP2E1, 5-HTR2A 1438A/G, and 5-HTR2A IVS2 were also determined.

Results

In 2000, the variant and wild-type ALDH2 groups exhibited little difference in terms of drinking frequency and problem drinking. Furthermore, some genotypes influenced only the variant group: ADH1B*2/*2 was associated with a lower drinking frequency, and CYP2E1 c2 allele was associated with an increased risk of problem drinking. In 2006, drinking frequency and risk of problem drinking were significantly lower in the variant group than in the wild-type group. However, the TPH AA genotype disturbed that difference, meaning that the subjects in the variant group had developed a similar level of risk of problem drinking to that in the wild-type group.

Conclusion

Korean university freshmen who were identified as a variant group drank as frequently as those in the wild-type group. For the subsequent 6 years they drank less frequently, thus decreasing the risk of problem drinking. However, that frequency drop was interrupted in those with gene polymorphisms such as ADH1B*1, CYP2E1 c2, and TPH A.     

Association of A313 G polymorphism (GSTP1*B) in the glutathione-S-transferase P1 gene with sporadic Parkinson's disease

Genetic predisposition, environmental toxins and aging contribute to Parkinson's disease (PD) multifactorial etiology. Weak environmental neurotoxic factors may accumulate over time increasing the disease risk in genetically predisposed subjects. Polymorphic genes encoding drug-metabolizing-enzymes (DMEs) are considered to account for PD susceptibility by determining individual toxic response variability. In this work, the allelic distributions and genotype associations of three major brain-expressed DMEs were characterized, in sporadic PD cases and controls. No significant association was found between CYP2D6 genotype and PD, but subjects with extensive metabolizer (EM) CYP2D6 phenotype, and the variant GSTP1 *B genotype were at significantly higher PD risk than the corresponding poor or intermediary metabolizers ( CYP2D6 poor metabolizer phenotype+intermediary metabolizers). A significant association was observed between the GSTP1*B allele and zygosity with PD ( GSTP1*A/*B – 51.58%/34.37%, odds ratio (OR) = 2.29; 95% confidence interval (95% CI) = 1.25–4.18; * B /* B – 6.32%/1.05%, OR = 10.67; 95% CI = 1.19–94.79). This association was particularly strong in the elder patients group (≥69 year) who showed double PD risk for GSTP1*B heterozygous, whilst GSTP1*B/*B homozygous were exclusively found amongst patients. An interaction between GSTM1 and GSTP1 was observed in this late onset PD group. The present results suggest that native GSTP1 encoding the fully active transferase variant should play a relevant role in dopaminergic neuroprotection.     

Plasma Concentration of Risperidone Showed a Correlation with Daily Dose, but not with Age nor Cytochrome P-450 2D6 Gene Polymorphisms in Japanese Schizophrenics

Background : Risperidone, a neuroleptic, is mainly metabolized by the enzyme cytochrome P-450 2D6 (CYP2D6), which has over 20 genetic polymorphisms, to its major active metabolite, 9-hydroxyrisperidone (9-OH-risperidone). The clinical outcome in risperidone treatment is highly dependent on the plasma concentration of risperidone.
Methods : In this study, in order to investigate whether individual plasma concentration of risperidone is affected by CYP2D6*4, CYP2D6*5 and major oriental mutation, CYP2D6*10A polymorphism, the genomic DNA from 53 subjects taking risperidone were analyzed by restriction fragment length polymorphism method for the determination of each genotype.
Results : Neither any plasma concentration of risperidone or 9-OH-risperidone nor metabolic ratio of risperidone/9-OH-risperidone was affected by CYP2D6 genotypes. "Plasma concentration of risperidone" and "plasma concentration of 9-OH-risperidone" showed a strong correlation with "risperidone dose/body weight" (r=0.60, p<0.0001; r=0.54, p<0.0001, respectively). "Age" of present subjects did not show any significant correlation with plasma concentration of risperidone (r=-0.018), 9-OH-risperidone (r=0.211) nor the metabolic ratio (r=-0.237, all p>0.05).
Conclusion : Based on these results that CYP2D6 genotypes and "age" showed no correlation with any plasma concentration of risperidone metabolites, it can be said that clinically the most important factor is to keep a small daily dose amount, regardless of the age of the subject. In this way, an unexpected high plasma concentration of risperidone can be avoided.     

Correlations between UGT2B712 gene polymorphisms and plasma concentrations of carbamazepine and valproic acid in epilepsy patients

Purpose

The study aims to detect the polymorphisms in uridine diphosphate glucuronyl transferase (UGT) 2B712 and investigate the corresponding effects on the blood concentrations of valproic acid (VPA) and carbamazepine (CBZ).

Some clinical pharmacological aspects of N-dipropylacetamide

The kinetics of the primary amide of valproic acid (VPA), i.e. dipropylacetamide, rapidly transformed into the corresponding acid in humans, are investigated and compared with valproate kinetics.In a group of healthy volunteers peak VPA concentration was reached within 5–14 hours of dipropylacetamide and within 1–2 hours of valproate administration. The plasma half-life appeared to be 8–12 hours for both compounds without significant differences. The relative bioavailability of the amide was 81.2% of valproate on average.In epileptics no correlation between plasma VPA levels and daily valproate or amide dose was observed; daily plasma valproic acid level fluctuations were significantly less wide during dipropylacetamide therapy.This compound seems to offer some advantages over sodium valproate, namely: slower absorption, stabler plasma levels through the day, 2 instead of 3 or 4 daily doses and hence less risk of drug defaulting.