通宣理肺丸对CYP2D6酶活性的影响

目的研究通宣理肺丸对CYP2D6酶活性的影响,探讨通宣理肺丸的代谢途径,为临床指导合理用药提供依据。方法筛选30名健康志愿者作为受试者。以右美沙芬作为CYP2D6的探针药,研究服用通宣理肺丸对人体内代谢酶CYP2D6活性的影响。采用高效液相色谱法-质谱(HPLC-MS/MS)法测定探针药及其代谢产物的血药浓度。连续服用14d通宣理肺丸。以曲线下面积(AUC0¹2)为指标,评价CYP2D6代谢酶的活性。结果受试者用药前CYP2D6代谢酶活性为6.1±1.5,服用通宣理肺丸后代谢酶活性为6.5±1.7,差异无统计学意义。结论服用通宣理肺丸对CYP2D6代谢酶活性没有明显影响。     

CYP2C19基因多态性对艾司唑仑在人体内药动学的影响

目的：研究健康人CYP2C19基因多态性对艾司唑仑药代动力学的影响。方法：39例健康受试者服用艾司唑仑并测定血药浓度。采用聚合酶链反应-限制性片段长度多态性PCR-RFLP方法确定受试者CYP2C19的基因型,分为野生纯合子、杂合子和突变纯合子。采用3P97软件计算药动学参数,SPSS13.0统计学软件比较CYP2C19基因型中药动学参数的差异。结果：采用PCR-RFLP方法对39例健康受试者的CYP2C19进行分型,杂合子有20例,突变纯合子有19例。CYP2C19基因杂合子强代谢型和弱代谢型比较结果,无统计学差异(P>0.05)。结论：CYP2C19的基因多态性对艾司唑仑的药动学没有显著性影响。     

CYP2C19多态性对奥美拉唑药代动力学的影响

目的:研究中国健康受试者细胞色素P4502C19(CYP2C19)多态性对奥美拉唑体内药代动力学的影响。方法:筛选12名健康男性和12名健康女性受试者,采用随机分组、双交叉的试验方案,每组分别服用一种奥美拉唑7d,洗脱期7d,第2周期交换用药。用LC-MS/MS方法测定每周期第1天和第7天多个时间点血药浓度,计算两种奥美拉唑的药代动力学参数。检测受试者基因位点CYP2C19*2(681G>A)和CYP2C19*3(636G>A),按照基因型分成快代谢型、中等代谢型和慢代谢型。结果:慢代谢型、中等代谢型和快代谢型在药代动力学参数t1/2、MRT0-t、CL、Vd、AUC0-t、AUC0-∞中存在显著性差异(P<0.05),连续给药后基因多态性对药物代谢的影响相对减小。结论:CYP2C19多态性与奥美拉唑的代谢密切相关,临床上应关注基因多态性对奥美拉唑代谢的影响。     

泮托拉唑对人肝脏药物代谢酶CYP1A2、NAT2和XO活性影响的研究

目的:探讨泮托拉唑对人肝脏药物代谢酶CYP1A2、NAT2和XO活性的影响,预测泮托拉唑与常用药物的相互作用,指导临床医师合理用药。方法:以咖啡因作为药物代谢酶CYP1A2、NAT2和XO的探针药物,以反相高效液相梯度洗脱法测定30名受试者服用泮托拉唑前后人尿液内咖啡因5种主要代谢产物的相对含量,采用代谢物的比率分别评价人肝脏药物代谢酶CYP1A2、NAT2和XO活性的变化。结果:受试者用药前CYP1A2、NAT2和XO平均活性为3.37±1.22、0.50±0.09、0.49±0.09;服用泮托拉唑7 d后CYP1A2、NAT2和XO平均活性为3.50±1.23、0.48±0.12、0.48±0.13;服药前后3种酶活性没有显著性差异(P>0.05)。结论:泮托拉唑对人肝脏药物代谢酶CYP1A2、NAT2和XO活性无明显影响,泮托拉唑可能不会影响与之合用的需经CYP1A2、NAT2和XO代谢的药物临床疗效。     

抗肿瘤药紫杉醇的代谢性相互作用

目的:通过大鼠肝微粒体体外代谢系统考察紫杉醇对CYP2C19酶活性的影响。方法:采用本实验室建立的大鼠肝微粒体体外代谢系统,用HPLC法测定CYP2C19酶活性,通过考察在体外代谢系统中加入紫杉醇和不加入紫杉醇时CYP2C19酶活性的变化,分析紫杉醇对CYP2C19酶活性的影响。结果:加入紫杉醇后,CYP2C19酶活性较不加入紫杉醇前降低了(17.6±2.6)%(P<0.01),差异有显著性。结论:紫杉醇对CYP2C19酶的活性有显著抑制作用,故临床将紫杉醇与经CYP2C19酶代谢的药物联合时,应注意代谢性相互作用对药物疗效的影响。     

吴茱萸次碱在人肝微粒体中对细胞色素P450酶的抑制作用

目的研究吴茱萸次碱(WZY)在人肝微粒体中对细胞色素P450酶的抑制作用。方法对照组和抑制组酶活性均用探针药测定,探针药物及其代谢产物用HPLC进行检测。用代谢产物与母药比值来表达酶的活性。结果加入50μmol·L-1吴茱萸次碱组CYP1A2,CYP2C19,CYP2E1和CYP2D6的活性显著降低,CYP3A4和CYP2C9活性无显著变化。结论吴茱萸次碱对CYP1A2,CYP2C19,CYP2E1和CYP2D6的活性有显著抑制作用,而对CYP2C9和CYP3A4的活性无显著影响。     

细胞色素P450 2C19单碱基突变位点CYP2C19m1的分析

目的:CYP2C19ml是引起CYP2C19酶活性缺陷的主要等位基因,有83％左右的慢代谢者含有CYP2C19ml等位基因,本文试图建立一步PCR测定CYP2C19ml等位基因的方法。方法:根据等位基因特异扩增(ASA)原理设计两对分别特异扩增野生型等位基因和突变型等位基因的引物,建立了一步PCR测定CYP2C19ml等位基因的方法。结果:对39位随机受试者进行了基因分型研究,发现3位CYP2C19ml纯合子、18位CYP2C19ml杂合子,其余18位为野生型纯合子。结论:说明效法能够用于测定CYP2C19ml等住基因,并且证明该法具有简便、快速和污染少的优点。     

细胞色素P450 2C19单碱基突变位点CYP2C19m1的分析

目的:CYP2C19ml是引起CYP2C19酶活性缺陷的主要等位基因,有83%左右的慢代谢者含有CYP2C19ml等位基因,本文试图建立一步PCR测定CYP2C19ml等位基因的方法。方法:根据等位基因特异扩增(ASA)原理设计两对分别特异扩增野生型等位基因和突变型等位基因的引物,建立了一步PCR测定CYP2C19ml等位基因的方法。结果:对39位随机受试者进行了基因分型研究,发现3位CYP2C19ml纯合子、18位CYP2C19ml杂合子,其余18位为野生型纯合子。结论:说明效法能够用于测定CYP2C19ml等住基因,并且证明该法具有简便、快速和污染少的优点。     

CYP2C19基因多态性对中国人体内兰索拉唑药代动力学及其5-羟基代谢通路的影响

目的:研究CYP2C19基因多态性对中国人体内兰索拉唑药代动力学及其5-羟基代谢通路的影响.方法:采用RFLP-PCR方法对12名健康受试者进行CYP2C19基因多态性检测,并采用液相色谱-质谱法(LC-MS)检测兰索拉唑体内血药浓度并计算相关的药代动力学参数,比较不同基因型受试者之间主要药代动力学参数以及AUCLpz...     

葛根素对人肝微粒体中细胞色素P450酶活性的影响

目的:研究葛根素对人肝微粒体中细胞色素P450 1A2(CYP1A2)、CYP3A4、CYP2C9、CYP2C19、CYP2D6、CYP2E1酶活性的影响.方法:分别以咖啡因、咪达唑仑、甲苯磺丁脲、氯唑沙宗、美托洛尔、美芬妥因为探针药,利用HPLC方法测定探针药与相应代谢产物的浓度,研究葛根素在人肝微粒体孵化体系中对CYP1A2、CYP3A4、CYP2C9、CYP2E1、CYP2D6、CYP2C19酶活性的影响.结果:在人肝微粒体反应体系中,0.1,0.2,0.4,0.8mmol·L-1葛根素使咖啡因的代谢产物的生成分别降低了(31±15)%(P＜0.01),(43±8)%(P＜0.05),(48±6)%(P＜0.05),(49±4)%(P＜0.05),0.05,0.1,0.2,0.4,0.8mmol·L-1葛根素使美托洛尔的代谢产物生成分别降低了(25±7)%(P＜0.01),(33±4)%(P＜0.05),(40±9)%(P＜0.01),(46±5)%(P<0.01),(72±9)%(P＜0.01);而对甲苯磺丁脲、美芬妥因、咪达唑仑和氯唑沙宗的代谢产物没有明显影响.结论:在人肝微粒体反应体系中,葛根素(0.1 mmol·L-1)对CYP1A2和CYP2D6酶活性有较明显的抑制作用;且随着葛根素浓度的增高,对这两种酶活性的抑制作用也随之增强,而对CYP2C9、CYP2C19、CYP3A4和CYP2E1酶活性没有影响.     

Association between blood carisoprodol:meprobamate concentration ratios and CYP2C19 genotype in carisoprodol-drugged drivers: decreased metabolic capacity in heterozygous CYP2C19*1/CYP2C19*2 subjects?

Carisoprodol is metabolized to meprobamate by the cytochrome P450 enzyme CYP2C19, encoded by the polymorphic CYP2C19 gene. Most studies on carisoprodol metabolism have been carried out on individuals phenotyped for CYP2C19 activity using the probe drug S-mephenytoin. We aimed to investigate whether the ratio of carisoprodol to meprobamate in a 'real life' setting could be predicted by CYP2C19 genotype or, more specifically, if high carisoprodol : meprobamate ratios in drugged drivers could be ascribed to the presence of mutant CYP2C19 alleles. From original material comprising 358 blood samples from apprehended drivers, two polarized groups were selected; a high-ratio group of 11 subjects where the carisoprodol : meprobamate ratio was >1 and a low-ratio control group of 23 subjects where the ratio was <0.31. Genotyping was carried out for the CYP2C19*2, CYP2C19*3 and CYP2C19*4 alleles. DNA samples from 94 healthy blood donors were used as reference material. The number of mutant alleles in the high-ratio and low-ratio groups was significantly higher and lower, respectively, than in the reference material. The increased number of mutant alleles in the high-ratio group was not due to the presence of many poor metabolizers, but to a high number of heterozygous individuals with the genotype CYP2C19*1/*2. This result indicates a gene dosage effect where the carisoprodol : meprobamate ratio reflects the number of active CYP2C19 alleles. The metabolism of carisoprodol to meprobamate is dependent on CYP2C19 genotype. Heterozygous individuals with the CYP2C19*1/*2 genotype have a reduced capacity for metabolizing carisoprodol, and should probably be regarded as intermediate metabolizers of this drug.     

CYP2C19 基因多态性与 6~ 14 岁儿童幽门螺杆菌感染铋剂四联方案 疗效的关系

目的:探讨 CYP2C19 基因多态性与 6~14 岁儿童幽门螺杆菌(Hp)感染铋剂四联方案疗效的关系。 方法:选取 2020 年 2 月至 2022 年 9 月我院消化内科门诊确诊为 Hp 感染的 138 例患儿为研究对象,均采用铋剂四联方案治疗(奥美拉唑+阿莫西 林+克拉霉素+枸橼酸铋钾)。 检测患儿 CYP2C19 基因多态性,并根据基因检测结果分为强代谢(EM)组、中间代谢(IM)组和弱 代谢(PM)组,比较 3 组患儿临床疗效、Hp 根除率及不良反应发生情况。 结果:患儿 CYP2C19 基因 EM 型、IM 型及 PM 型的分 布频率分别为 39. 13%、42. 75%、18. 12%。 IM 组和 PM 组总有效率及 Hp 根除率均高于 EM 组(P<0. 05),IM 组和 PM 组总有效 率及 Hp 根除率比较差异无统计学意义(P>0. 05)。 EM 组和 IM 组不良反应总发生率均低于 PM 组(P<0. 05),EM 组和 IM 组不 良反应总发生率比较差异无统计学意义(P>0. 05)。 结论:不同 CYP2C19 基因表型的 Hp 感染患儿通过铋剂四联方案治疗后的 疗效及不良反应存在差异,IM 型及 PM 型患儿疗效较显著,EM 型患儿疗效较差,但 PM 型患儿易出现不良反应。     

黄连解毒汤对人细胞色素P450酶6个亚型的体外抑制作用研究

目的:研究黄连解毒汤对人肝微粒体6个亚型CYP1A2、CYP2C8、CYP2C9、CYP2C19、CYP2D6和CYP3A4的体外抑制作用。方法:采用液相色谱-串联质谱法(LC-MS/MS)同时测定对乙酰氨基酚、6α-羟基紫杉醇、4-羟基双氯芬酸、4-羟基美芬妥英、右啡烷、1-羟基咪达唑仑和6β-羟基睾酮,分别代表CYP1A2、CYP2C8、CYP2C9、CYP2C19、CYP2D6和CYP3A4的活性;黄连解毒汤提取物和7种混合探针底物在人肝微粒体中共同孵育,并计算其IC50值表示对CYP450酶的抑制程度。结果:在人肝微粒体体外孵育体系中,黄连解毒汤对CYP2D6的IC50值为3.54μg/mL,对CYP1A2的IC50值为10.8μg/mL,对CYP2C8、CYP2C9、CYP2C19、CYP3A4_T和CYP3A4_M亚酶的IC50值依次为67.7、299、530、199和607μg/mL。结论:在正常剂量下,黄连解毒汤对人肝微粒体CYP2D6和1A2可能有抑制作用,对人肝微粒体CYP2C8、CYP2C9、CYP2C19和CYP3A4无明显抑制作用。     

幽门螺杆菌根除疗效与CYP2C19基因多态性的相关性研究

目的：研究和分析幽门螺杆菌根除疗效与CYP2C19基因多态性的相关性。方法：收集慢性胃溃疡患者100例,随机分为观察组与对照组,各50例,两组患者均使用克拉霉素和阿莫西林进行治疗后,对照组患者使用埃索美拉唑进行治疗,观察组患者使用兰索拉唑进行治疗,将两组患者的CYP2C19基因型进行测定和对比,在治疗结束后对幽门螺杆菌的根除效果进行检测。结果：观察组患者和对照组患者的幽门螺杆菌根除率,以P＞0.05表示差异无统计学意义;通过CYP2C19基因分型,对照组患者中弱代谢型、中间代谢型和快代谢型的幽门螺杆菌根除率无显著差异（P＞0.05）;而观察组弱代谢型的根除率明显高于快代谢型（P<0.05）。结论：在幽门螺杆菌的根除治疗过程中,通过CYP2C19基因多态性的检测,能够提供有效的用药选择参考价值。     

In vitro and in vivo assessment of the effect of dalcetrapib on a panel of CYP substrates

ABSTRACT

Objective: The primary objective of this study was to investigate the drug–drug interaction potential of dalcetrapib on drugs metabolized via major cytochrome P450 (CYP) isoforms using both in vitro and clinical approaches. A secondary objective was to investigate the safety and tolerability of dalcetrapib alone or co-administered either with a combination of five probe drugs or with rosiglitazone.

Research design and methods: Human liver microsomes and a panel of substrates for CYP enzymes were used to determine IC₅₀ for inhibition of CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. In addition, two drug–drug interaction studies were conducted in healthy males: dalcetrapib 900?mg plus the Cooperstown 5?+?1 drug cocktail, which includes substrates for CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4, and dalcetrapib 900?mg plus rosiglitazone, a substrate for CYP2C8. Pharmacokinetic and safety parameters were assessed.

Results: In vitro, dalcetrapib was inhibitory to all CYP enzymes tested. IC₅₀ values ranged from 1.5?±?0.1?μM for CYP2C8 to 82?±?4?μM for CYP2D6. Co-administration of dalcetrapib plus drug cocktail showed no clinically relevant effect of 900?mg dalcetrapib on activity of CYP1A2, CYP2C19, CYP2D6, CYP2C9, or CYP3A4 following repeated administration. Co-administration of dalcetrapib plus rosiglitazone showed no clinically relevant effect of dalcetrapib 900?mg on activity of CYP2C8. Dalcetrapib was generally well tolerated.

Conclusions: Although in vitro studies indicated that dalcetrapib inhibits CYP activity, two clinical studies showed no clinically relevant effect on any of the major CYP isoforms at a 900?mg dose, which is higher than the 600?mg dose being explored in phase III studies. Dalcetrapib was generally well tolerated in these studies. However, these studies were limited to a small number of healthy males; additional, larger studies are necessary to study its safety.     

Evaluation of cytochrome P450 probe substrates commonly used by the pharmaceutical industry to study in vitro drug interactions.

Pharmaceutical industry investigators routinely evaluate the potential for a new drug to modify cytochrome p450 (p450) activities by determining the effect of the drug on in vitro probe reactions that represent activity of specific p450 enzymes. The in vitro findings obtained with one probe substrate are usually extrapolated to the compound's potential to affect all substrates of the same enzyme. Due to this practice, it is important to use the right probe substrate and to conduct the experiment under optimal conditions. Surveys conducted by reviewers in CDER indicated that the most common in vitro probe reactions used by industry investigators include the following: phenacetin O-deethylation for CYP1A2, coumarin 7-hydroxylation for CYP2A6, 7-ethoxy-4-trifluoromethyl coumarin O-dealkylation for CYP2B6, tolbutamide 4'-hydroxylation for CYP2C9, S-mephenytoin 4-hydroxylation for CYP2C19, bufuralol 1'-hydroxylation for CYP2D6, chlorzoxazone 6-hydroxylation for CYP2E1, and testosterone 6 beta-hydroxylation for CYP3A4. We reviewed the validation information in the literature on these reactions and other frequently used reactions, including caffeine N3-demethylation for CYP1A2, S-mephenytoin N-demethylation for CYP2B6, S-warfarin 7'-hydroxylation for CYP2C9, dextromethorphan O-demethylation for CYP2D6, and midazolam 1'-hydroxylation for CYP3A4. The available information indicates that we need to continue the search for better probe substrates for some enzymes. For CYP3A4-based drug interactions it may be necessary to evaluate two or more probe substrates. In many cases, the probe reaction represents a particular enzyme activity only under specific experimental conditions. Investigators must consider appropriateness of probe substrates and experimental conditions when conducting in vitro drug interaction studies and when extrapolating the results to in vivo situations.     

云南地区冠心病患者CYP2C19基因多态性分布研究

目的： 探讨云南地区冠心病患者CYP2C19基因多态性分布,并比较不同地区和民族间CYP2C19基因多态性的分布,为个体化药物治疗提供理论依据。方法： 选取2016年1月至2017年12月就诊于云南省第一人民医院,拟使用氯吡格雷抗血小板治疗的冠心病患者共978例,采用数字荧光分子杂交技术检测CYP2C19基因多态性,并比较不同地区、民族间的CYP2C19基因分布情况。结果： 在978例冠心病患者中,CYP2C19*1/*1、CYP2C19*2/*2、CYP2C19*3/*3、CYP2C19*17/*17、CYP2C19*1/*2、CYP2C19*1/*3*、CYP2C19*1/*17、CYP2C19*2/*3、CYP2C19*2/*17、CYP2C19*3/*17基因型所占比例分别为37.52%、11.35%、0.51%、0.10%、39.26%、5.52%、1.02%、3.78%、0.82%、0.10%;等位基因CYP2C19*1、CYP2C19*2、CYP2C19*3、CYP2C19*17的分布频率分别为60.43%、33.28%、5.21%、1.07%;CYP2C19代谢型（超快、快、中间、慢）所占比例分别为1.12%、37.52%、45.70%、15.64%。CYP2C19基因型、代谢型与北京、南京、淮海、重庆比较,差异无统计学意义（P>0.05）,而与河南、陕西、广东比较有显著差异（P<0.05）;与蒙古族比较,差异无统计学意义（P>0.05）,而与维吾尔族、哈萨克族、壮族比较有显著差异（P<0.05）。结论： 云南地区CYP2C19基因存在多态性,功能缺失型等位基因分布频率较高,建议使用氯吡格雷抗血小板进治疗冠心病患者时,对CYP2C19基因型进行分析,以实施个体化给药治疗。     

Reliability of the omeprazole hydroxylation index for CYP2C19 phenotyping: possible effect of age, liver disease and length of therapy

AIMS: To evaluate the reliability of the omeprazole hydroxylation index as a marker for polymorphic CYP2C19 activity in a Japanese population of healthy young subjects (n = 78) and patients with peptic ulcer (n = 72). METHODS: Healthy subjects were administered a single dose of omeprazole (20 mg), whereas patients received 20 mg daily for at least 1 week. The ratio of the serum concentration of omeprazole to hydroxyomeprazole at 3 h postdose was determined and used as a measure of CYP2C19 activity. The CYP2C19 wild type (wt) gene and four mutant alleles associated with the poor metaboliser phenotype of (S)-mephenytoin, CYP2C19*2 in exon 5, CYP2C19*3 in exon 4, CYP2C19m4 in exon 9, and CYP2C19m3 in the initial codon were analysed. RESULTS: In the healthy volunteer study there was complete concordance between genotype and phenotype. However, eight of the patients who had the EM genotype had a high value for their hydroxylation index, and were classified as phenotypic PMs. No CYP2C19m4 and CYP2C19m3 mutations were detected in the eight mismatched patients. They were all genotypic heterozygous EMs, elderly (> or = 65 years) and/or had hepatic disease. Therefore, impaired CYP2C19 activity combined with partial saturation of omeprazole metabolism during multiple dosing may have contributed to the discrepancy between CYP2C19 genotyping and phenotyping. CONCLUSION: Although omeprazole has been used instead of mephenytoin as a probe for polymorphic CYP2C19, it does not appear to be reliable enough for clinical application in Japanese patients.     

Stereospecific analysis of omeprazole in human plasma as a probe for CYP2C19 phenotype

Omeprazole is a class referred to as proton pump inhibitor; it acts to regulate acid production in the stomach and is used to treat various acid-related gastrointestinal disorders. In the liver, it is metabolized to varying degrees by several cytochrome P-450 (CYP) isoenzymes which are further categorized into subfamilies of related polymorphic gene products. The metabolism of omeprazole is to a large extent dependent on CYP3A4 and CYP2C19. Omeprazole is metabolized to two major metabolites, 5-hydroxyomeprazole (CYP2C19) and omeprazole sulfone (CYP3A4). Minor mutations in CYP2C19 affect its activity in the liver and, in turn, the metabolic and pharmacokinetic profiles of omeprazole. The frequency of CYP2C19 poor metabolizers in population of Asian descent has been reported to range from 10 to 20%. Accordingly, results from population studies indicate that omeprazole can be used as a probe drug for phenotyping CYP2C19. The optical isomers of omeprazole show a clear difference in their metabolism by human liver microsomes. This study demonstrates the stereospecific analysis of omeprazole in human plasma as a probe drug of CYP2C19 phenotyping. The chiral separation of omeprazole was achieved on a chiral column with circular dichroism (CD) detection and LC/MS. A good resolution of enantiomers was obtained. The column used for chiral separation was CHIRALPAK AD-RH column (4.6×150 mm) using phosphate buffer and (or ammonium acetate) acetonitrile as an eluent. After a single oral dose of omeprazole (20 mg), the plasma concentrations of the separate enantiomers of omeprazole were determined for 3.5 h after drug intake. The present study is useful because of the part polymorphism plays in the therapeutic effectiveness of proton pump inhibitors during the treatment of acid-related diseases.