CYP2C19基因多态性对艾普拉唑在中国人体内的药效学影响

目的：观察中国汉族人细胞色素P450（CYP）2C19的基因多态性及其对艾普拉唑药效学的影响。方法：测定25例口服艾普拉唑肠溶片5mg/d,2～4周的活动性十二指肠溃疡患者CYP2C19基因的代谢表现型,将其分为纯合子强代谢型（homEM）、杂合子强代谢型（hetEM）和弱代谢型（PM）3种表现型,再通过胃镜检查结果判断治疗效果,建立两者的相关性。结果：将CYP2C19基因的homEM型、hetEM型和PM型3种表现型患者用药后2周及4周的总有效率分别进行两两比较,差异均无统计学意义（P＞0.05）。结论：在中国汉族人中,CYP2C19基因多态性对艾普拉唑治疗十二指肠溃疡的疗效无显著影响。     

CYP2C19基因多态性对奥美拉唑在中国人体内的药物动力学和药效学的影响

目的研究CYP2C19基因多态性对奥美拉唑在中国人体内的药物动力学和药效学的影响。方法在18例幽门螺杆菌感染阴性的健康志愿者中,应用聚合酶链反应-限制性片段长度多态性(PCR-RFLP)方法确定CYP2C19基因型,分为纯合子强代谢型(homEM),杂合子强代谢型(hetEM)和弱代谢型(PM)3组,每组6人。受试者口服奥美拉唑20 mg.d-1,连续8 d。分别在服药后d 1和d 8,应用高效液相色谱法测定奥美拉唑血药浓度,采用24 h胃内pH监测仪监测胃内pH情况。结果服用奥美拉唑d1,PM组的血药浓度-时间曲线下面积(AUC)高于homEM组和hetEM组,在三种基因型之间的相对比率为1∶1.1∶4.2(homEM∶hetEM∶PM);在服药d 8,PM组的AUC值也高于homEM组和hetEM组,在三种基因型之间的相对比率为1.0∶1.3∶3.3(homEM∶hetEM∶PM)。在服药d1,24 h胃内pH中位值、pH>3的总时间和pH>4的总时间在三种基因型间差异有显著性;在服药d 8,这些参数在PM组高于其它两组。结论CYP2C19基因多态性对奥美拉唑在中国人体内的药物动力学和药效学有明显影响。     

中国人群中CYP2C19基因多态性对质子泵抑制剂三联疗法根除幽门螺杆菌疗效影响的Meta分析

目的：系统评价中国人群中药物代谢酶CYP2C19基因多态性与质子泵抑制剂三联疗法根除幽门螺杆菌疗效的关系,为临床治疗提供循证参考。方法：检索PubMed、Embase、CBM、CNKI、WanFang data、CQVIP等数据库,收集CYP2C19基因多态性与质子泵抑制剂三联疗法根除幽门螺杆菌感染的临床文献。根据纳入和排除标准筛选文献、评价和提取数据后,采用RevMan 5.3和Stata 13.1软件进行Meta分析。结果：共纳入12篇文献,包含1 851例对象。Meta分析结果显示：不考虑质子泵抑制剂类型,CYP2C19强代谢型（EM）、中间代谢型（IM）与弱代谢型（PM）的幽门螺杆菌根治率存在统计学差异[EM vs. IM：OR=0.57,95%CI（0.36,0.88）,P<0.05;EM vs. PM：OR=0.39,95%CI（0.25,0.59）,P<0.05;IM vs. PM：OR=0.54,95%CI（0.35,0.86）,P<0.05]。亚组分析表明含奥美拉唑的三联方案中,EM型幽门螺杆菌根治率明显低于IM型[OR=0.21,95%CI（0.11,0.39）,P<0.05],同样结果也发生在EM与PM之间[OR=0.12,95%CI（0.04,0.35）,P<0.05],但IM型与PM型间无差异。其他质子泵抑制剂如埃索美拉唑、兰索拉唑、雷贝拉唑等未发现上述差异。结论：中国人群中CYP2C19基因多态性可能影响奥美拉唑三联疗法根除幽门螺杆菌的疗效,但不影响埃索美拉唑、兰索拉唑、雷贝拉唑等质子泵抑制剂的根除效果。     

中国人群中CYP2C19基因多态性对质子泵抑制药治疗消化性溃疡疗效影响的Meta分析

摘 要 目的：采用Meta分析方法评价中国人群中药物代谢酶CYP2C19基因多态性与质子泵抑制药对消化性溃疡愈合率的关系,以期为临床用药与基因检测提供循证依据。方法: 检索SinoMed、中国知网、维普期刊数据库、万方数据库、PubMed、Embase中有关CYP2C19基因多态性与质子泵抑制药治疗消化性溃疡的临床研究文献。根据纳入和排除标准筛选文献、评价和提取数据后,采用RevMan 5.3与Stata 13.0软件进行Meta分析。结果: 共纳入8篇文献,包含1 197例对象。Meta分析结果显示：不考虑质子泵抑制药类型,CYP2C19强代谢型（EM）的消化性溃疡愈合率低于与中间代谢型（IM）（OR=0.63,95%CI：0.46~0.86,P<0.05）,EM型的消化性溃疡愈合率低于与弱代谢型（PM）（OR=0.45,95%CI：0.29~0.69,P<0.05）,但IM型与PM型消化性溃疡愈合率的差异无统计学意义（OR=0.68,95%CI：0.44~1.04,P>0.05）。亚组分析仅发现同样结果存在于奥美拉唑中,EM型消化性溃疡愈合率低于IM型低（OR=0.59,95%CI：0.36~0.97,P<0.05）,EM型消化性溃疡愈合率亦低于PM型（OR=0.29,95%CI：0.13~0.62,P<0.05）,但IM型与PM型的差异无统计学意义（P>0.05）。其他质子泵抑制药如雷贝拉唑、埃索美拉唑、艾普拉唑等未发现上述差异。结论: 中国人群中CYP2C19基因多态性影响奥美拉唑的消化性溃疡愈合率疗效,但不影响埃索美拉唑、雷贝拉唑、艾普拉唑等其他质子泵抑制药的疗效。因此,在应用奥美拉唑治疗消化性溃疡时,有必要对患者的CYP2C19进行基因检测,以指导个体化给药方案的制订。     

CYP2C19基因型对雷贝拉唑在健康人中药动学的影响

目的:研究雷贝拉唑在体内的代谢与CYP2C19酶的相关性,预测CYP2C19基因多态性对雷贝拉唑抑酸效应的影响。方法:采用开放、对照研究。根据PCR-RFLP方法确定的CYP2C19基因型将36例志愿者分为2组,CYP2C19强代谢型(EMs)组(n=24)及弱代谢型(PMs)组(n=12)。给予雷贝拉唑20mg单剂量口服,收集服药后12h的血样,用高效液相色谱(HPLC)法测定雷贝拉唑及其代谢产物硫醚雷贝拉唑、去甲基硫醚雷贝拉唑的血药浓度并作药动学分析。结果:硫醚雷贝拉唑的tmax和t1/2为EMs组(3.0±s0.6)h和(1.9±0.4)h;PMs组(3.6±0.9)h和(3.0±0.8)h,P<0.05和P<0.01,雷贝拉唑、硫醚雷贝拉唑以及去甲基硫醚雷贝拉唑的cmax,AUC,Cl/F2组差异均无显著意义。结论:雷贝拉唑的代谢主要不依赖于CYP2C19酶。     

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。     

CYP2C19基因多态性对雷贝拉唑与奥美拉唑四联治疗幽门螺杆菌阳性胃溃疡疗效的影响

目的:分析CYP2C19基因多态性对雷贝拉唑和奥美拉唑四联治疗幽门螺杆菌(Hp)阳性胃溃疡疗效的影响。方法:选取Hp阳性胃溃疡患者168例,随机分为2组。观察组接受雷贝拉唑四联疗法,对照组接受奥美拉唑四联疗法,治疗结束4周后比较2组患者胃肠道症状改善情况、临床疗效、Hp根除率及不良反应发生情况。同时利用DNA微阵列芯片法检测患者的CYP2C19基因型,观察基因型对两组药物疗效的影响。结果:观察组治愈率72.62%,总有效率89.28%,Hp根除率95.23%,对照组治愈率58.34%,总有效率72.62%,Hp根除率86.90%,两组差异显著(P<0.05或P<0.01)。观察组中,快代谢型(EM)治愈率61.12%,中间代谢型(IM)80.00%,弱代谢型(PM)84.62%,EM型与IM及PM型间差异极显著(P<0.01),IM型与PM型之间无显著性差异(P>0.05)。对照组中,EM型治愈率44.74%,IM型64.71%,PM型83.34%,3种代谢型间的治愈率差异极显著(P<0.01)。相同代谢型患者治愈率两组间比较,PM型无明显差异(P>0.05),但EM型与IM型观察组均明显高于对照组(P<0.05)。结论:雷贝拉唑四联疗法较奥美拉唑四联疗法治疗Hp阳性胃溃疡根除率更高,疗效更显著,安全性相当,且受CYP2C19基因型影响程度较小,疗效更稳定,值得临床推荐。     

细胞色素P450 2C19基因多态性对奥美拉唑胶囊抑酸效果的影响

目的研究细胞色素P4502C19（CYP2C19）基因多态性对奥美拉唑胶囊抑酸效果的影响。方法在15名幽门螺杆菌感染阴性的健康志愿者中，用聚合酶链反应-限制性片段长度多态性方法确定CYP2C19基因型，分为纯合子强代谢型（hom EM），杂合子强代谢型（het EM）和弱代谢型（PM）3组，每组5人。受试者口服奥美拉唑每天20mg，连续8天。分别在服药第1天和第8天，用24h胃内pH测定仪分析24h胃内pH中位值、pH〉4及pH〉3的总时间。结果24h胃内pH中位值、pH〉4和pH〉3的总时间，PM组显著高于hom EM组和het EM组（P〈0．05）。hom EM组和her EM组的24h胃内pH监测参数，在服药第8天显著高于第1天（P〈0．05）。夜间抑酸效果，PM组也优于hom EM组和het EM组（P〈0．05）。结论CYP2C19基因多态性对奥美拉唑的抑酸效果及夜间酸突破现象均有明显影响。     

苯并咪唑类质子泵抑制剂的药理学研究进展

苯丙咪唑类质子泵抑制剂(Protonpumpinhibitor,PPI)雷贝拉唑、奥美拉唑、兰索拉唑和泮托拉唑在肝脏中不同程度地被细胞色素P450(CYP)同功酶代谢(参与CYP代谢的主要同功酶为CYP2C19和CYP3A4),它们药物代谢和药代动力学的不同会对其药效学(如抑制胃酸分泌,对胃泌素的影响)及可能出现的药物相互作用产生不同影响。1CYP与基因多态性对PPI药效的影响PPI在肝脏中的氧化代谢是由特异性或选择性CYP同功酶来催化的,根据基因多态性表达产物又可将CYP同功酶进一步分为不同类型。参与PPI代谢的同功酶主要有CYP2C19和CYP3A4。CYP2C19…     

CYP2C19基因多态性对艾司奥美拉唑治疗胃食管反流病疗效的影响

目的 研究CYP2C19基因多态性对艾司奥美拉唑治疗胃食管反流病疗效的影响。方法 选择2019年1月~ 2019年8月就诊于某三甲医院消化内科胃食管反流病92例患者作为研究对象。采用DNA微阵列芯片法对患者进行基因分型,其中32例为强代谢型EM,36例为中等代谢型IM,24例为弱代谢型PM。应用注射用艾司奥美拉唑钠40mg qd治疗2周方案,分别于第7天、第14天测定24小时胃内pH值和消化内镜检查临床疗效。结果 在治疗艾司奥美拉唑第7天、第14天时,EM、IM、PM代谢型患者pH＞4总时间百分比有显著性差异（P＜0.05）;在治疗艾司奥美拉唑第14天,EM、IM、PM代谢型患者临床疗效有显著性差异（P＜0.05）。结论艾司奥美拉唑治疗胃食管反流病疗效的抑酸作用和疗效与CYP2C19基因多态性密切相关。     

Pharmacodynamic effects and kinetic disposition of rabeprazole in relation to CYP2C19 genotype in healthy Chinese subjects

AIM: To investigate whether the pharmacodynamics and pharmacokinetics of rabeprazole are dependent on CYP2C19 genotype status in healthy Chinese Han subjects. METHODS: The CYP2C19 genotype status of healthy Chinese Han volunteers was determined using the polymerase chain reaction-restriction fragment length polymorphism method. Twenty healthy subjects volunteered to participate in the study. There were seven homozygous extensive metabolizers (homEM), six heterozygous extensive metabolizers (hetEM), and seven poor metabolizers (PM). All subjects were Helicobactor pylori-negative, which was determined by sero-logy and 13C-urea breath tests. Rabeprazole (20 mg) was taken orally once daily in the morning for 8 days, and intragastric pH values were monitored for 24 h by Digitrapper pH after day 1 (single dose) and day 8 (repeated dose). Meanwhile, blood samples were collected at various time-points for 24 h after administration. The serum concentrations of rabeprazole were measured using high-performance liquid chromatography. RESULTS: The mean area under the curve (AUC) values for rabeprazole differed among the three different genotype groups, with a relative ratio of 1.0, 1.3, and 1.8 after a single dose and 1.0, 1.1, and 1.7 after repeated doses in the homEM, hetEM, and PM groups, respectively. Mean AUC values for rabeprazole after a single dose and after repeated doses were significantly different between the homEM and PM groups, but not between the homEM and hetEM or hetEM and PM groups. No significant differences in intragastric pH median, pH>4 total time, and pH>4 time percentage of 24 h, were observed among the three different genotype groups after a single dose or after repeated doses of rabeprazole. CONCLUSION: In healthy Chinese Han subjects, the pharmacokinetics of rabeprazole are dependent on a certain degree on CYP2C19 genotype status; however, the acid-inhibitory efficacy of rabeprazole is not influenced significantly by CYP2C19 genetic polymorphism.     

Effects of genotypic differences in CYP2C19 status on cure rates for Helicobacter pylori infection by dual therapy with rabeprazole plus amoxicillin.

Rabeprazole is a potent proton pump inhibitor and is mainly reduced to thioether rabeprazole by a non-enzymatic pathway and partially metabolized to demethylated rabeprazole by CYP2C19 in the liver. We intended to determine a cure rate for Helicobacter pylori infection by dual rabeprazole/amoxicillin therapy in relation to CYP2C19 genotype status prospectively. Ninety-seven patients with gastritis and H. pylori infection completed the dual therapy with 10 mg of rabeprazole bid and 500 mg of amoxicillin tid for 2 weeks. At 1 month after treatment, cure of H. pylori infection was assessed on the basis of histology, a rapid urease test, culture, polymerase chain reaction (PCR), and 13C-urea breath test. CYP2C19 genotype status was determined by a PCR-restriction fragment length polymorphism method. Of the 97 patients, 33 were homozygous extensive metabolizers (homEM), 48 were heterozygous extensive metabolizers (hetEM), and 16 were poor metabolizers (PM). Cure of H. pylori infection was achieved in 79 of the 97 patients (81.4%, 95%CI = 71.9-88.7). Significant differences in cure rates among the homEM, hetEM, and PM groups were observed; 60.6% (95%CI = 42.1-77.3), 91.7% (95%CI = 80.0-97.7), and 93.8% (95%CI = 69.8-99.8), respectively (P = 0.0007). Twelve patients without cure after initial treatment (10 homEMs and 2 hetEMs) were successfully retreated with rabeprazole 10 mg q.i.d. and amoxicillin 500 mg q.i.d. for 2 weeks. The cure rates for H. pylori infection by dual rabeprazole/amoxicillin therapy depended on the CYP2C19 genotype status. This dual therapy appears to be effective for hetEM and PM patients. However, high dose dual rabeprazole/amoxicillin therapy was effective even for homEM patients. Therefore, the genotyping test of CYP2C19 appears to be a clinically useful tool for the optimal dual treatment with rabeprazole plus amoxicillin.     

Pharmacogenomics of proton pump inhibitors

Proton pump inhibitors (PPIs), such as omeprazole, lansoprazole, rabeprazole, esomeprazole, and pantoprazole, are metabolized by cytochrome P450 isoenzyme 2C19 (CYP2C19) in the liver. There are genetic differences that affect the activity of this enzyme. The genotypes of CYP2C19 are classified into three groups: homozygous extensive metabolizer (homEM), heterozygous extensive metabolizer (hetEM), and poor metabolizer (PM). The pharmacokinetics and pharmacodynamics of PPIs differ among the different CYP2C19 genotype groups. Plasma PPI and intragastric pH levels during PPI treatment are the lowest in the homEM group and the highest in the PM group. These CYP2C19 genotype-dependent differences in pharmacokinetics and pharmacodynamics of PPIs are reflected in the cure rates for gastroesophageal reflux disease and Helicobacter pylori infection with PPI-based therapies. The CYP2C19 genotyping test is a useful tool for deciding on the optimal treatment regimen using a PPI, including a dual (PPI plus antibiotic) or a triple (PPI plus two antibiotics) therapy.     

Pharmacodynamic effects and kinetic disposition of rabeprazole in relation to CYP2C19 genotypes

BACKGROUND: S-mephenytoin 4'-hydroxylase (CYP2C19) catalyses the metabolism of rabeprazole to some extent. Based on the metabolic and pharmacokinetic differences among other proton pump inhibitors such as omeprazole, lansoprazole and pantoprazole, rabeprazole appears to be the least affected proton pump inhibitor by the CYP2C19-related genetic polymorphism. AIM: To determine whether the pharmacodynamic effects of rabeprazole on intragastric pH and serum gastrin levels, and its pharmacokinetics depend on the CYP2C19 genotype status. METHODS: Eighteen healthy subjects, whose CYP2C19 genotype status was previously determined, participated in the study. They consisted of six each of homozygous extensive metabolisers (homo EMs), heterozygous extensive metabolisers (hetero EMs), and poor metabolisers (PMs). Helicobacter pylori status was determined by serology. After a single oral dose of 10 mg or 20 mg rabeprazole or water only (baseline data), intragastric pH values were monitored for 24 h. Plasma levels of rabeprazole and serum gastrin were also measured for 24 h post-dose. RESULTS: Five homo EM, six hetero EM and four PM subjects were H. pylori-negative. After rabeprazole administration, significant differences in intragastric mean pH values, serum gastrin AUC(0-24) and plasma levels of rabeprazole were observed among the three different genotype groups. CONCLUSION: The pharmacodynamic effects of rabeprazole and its pharmacokinetics depend on the CYP2C19 genotype status.     

Clinical impact of CYP2C19 polymorphism on the action of proton pump inhibitors: a review of a special problem

Proton pump inhibitors (e.g. omeprazole/esomeprazole, lansoprazole, pantoprazole, rabeprazole) have a prominent role in the short- and long-term management of acid-related intestinal disease. They are eliminated by the hepatic route and the polymorphic CYP2C19 is involved in their metabolism. Three phenotypes have been identified in various populations: extensive metabolizers (homEM), poor metabolizers (PM) and individuals carrying one wild type and one mutant allele (hetEM). Therefore, systemic drug exposure (AUC) varies widely between these three populations and the AUC for omeprazole, lansoprazole and rabeprazole are approximately 7.5-, 4.5- and 4-fold higher in PM than in homEM. Since the pharmacodynamic response to proton pump inhibitors (PPIs) is related to their AUC, intragastric pH is much more elevated in PM (median around 6) and hetEM (4 - 5) than in homEM (3 - 4). This genotype-dependent increase in AUC and intragastric pH has clinical consequences because the healing rate in peptic ulcer (PU, target pH > or = 3) and gastroesophageal reflux disease (GERD, target pH > or = 4) and the eradication of Helicobacter pylori (Hp) depend on a long-lasting (> or = 16 hours) and effective inhibition of acid secretion. Several clinical studies have shown that PM and hetEM benefit from an approximately 18% higher Hp eradication rate compared to homEM when standard dosages of PPIs are administered orally. In our own study with lansoprazole (+ amoxicillin, clarithromycin, metronidazole) the eradication rates were 100, 98 and 80% in PM, hetEM and homEM, respectively, and in patients with GERD treated with lansoprazole (30 mg/day) the healing rates after 8 weeks were much higher in PM (85 - 100%) and hetEM (68 - 95%) than in homEM (46 - 77%). In a further study with esomeprazole (40 mg/day) in 205 patients with GERD we were surprised to observe that the healing rate after 4 weeks was not dependent on the CYP2C19 genotype. In an accompanying pharmacokinetic trial in 10 patients with GERD, both esomeprazole and 5-OH-esomeprazole (formed by CYP2C19) plasma levels and those of omeprazole-sulfone (formed by CYP3A4) were determined. Based on the calculated metabolic ratios it could be shown that CYP3A4 plays a major role in kinetics of esomeprozale, particularly after multiple dosing when there is a metabolic shift in favor of the formation of the sulfone. In conclusion, for most PPIs the activity of CYP2C 19 determines the level of drug exposure (AUC), pharmacodynamic response (elevation of intragastric pH and serum levels of gastrin) and clinical outcome (Hp eradication, healing rates of PU and GERD). Thus, a genotype-adjusted dosage regimen will improve therapeutic efficacy of PPIs.     

Interphenotype differences in disposition and effect on gastrin levels of omeprazole--suitability of omeprazole as a probe for CYP2C19.

1. Fourteen healthy Swedish Caucasian subjects were given 20 mg of omeprazole orally each morning for 8 days. The subjects included five poor metabolisers (PM) of S-mephenytoin, four heterozygous extensive metabolisers (hetEM) and five subjects with a very rapid metabolism (rapidEM). 2. After the first dose, the relative mean areas under the plasma concentration vs time curve (AUC) of omeprazole in rapidEM, hetEM and PM were 1:3.7:20 (all different, P < 0.001). A similar relation was seen in the AUC(0,10 h) of the sulphone metabolite (1:3:12). Concentrations of hydroxyomeprazole were higher in EM than in PM confirming that the hydroxy, but not the sulphone metabolite, is formed by the S-mephenytoin hydroxylase (CYP2C19). After 8 days of treatment, the differences between groups were similar. 3. After both the first and the eighth doses, the omeprazole/hydroxyomeprazole plasma concentration ratio, determined 3 h after drug intake, correlated with the mephenytoin S/R ratio (rs = 0.94; P < 0.001; n = 14) suggesting that omeprazole might be used to phenotype for CYP2C19. 4. After the first dose of omeprazole, there was no difference in the AUC(0,10 h) of plasma gastrin between the three groups. From the first to the eighth dose, the AUC(0,10) of gastrin increased significantly in both hetEM and PM, while there was no change in the rapidEM. After the eighth dose, the AUC(0,10) of gastrin correlated significantly with the AUC of omeprazole in plasma (rs = 0.79; P < 0.01; n = 13).     

细胞色素P2C19检测与消化性溃疡个体化治疗和PPI合理应用

质子泵抑制药(PPI)的抑酸作用是消化性溃疡治疗的基础,既有利于溃疡面愈合,也为抗生素根除幽门螺杆菌创造合适的pH条件;然而相同剂量的PPI对不同患者效果不同。PPI的代谢酶为细胞色素(CY)P2C19酶,由CYP2C19表达产生。在对PPI反应较好的患者中该基因常发生突变,成为CYP2C19*2和CYP2C19*3。由于该突变基因所表达的蛋白质无功能,所以CYP2C19酶整体活性降低,个体对PPI代谢能力减弱,使PPI可作用更长时间。个体依据基因型及PPI代谢的速率可分为纯合快代谢型、杂合快代谢型和慢代谢型。快代谢型消化性溃疡(PU)患者通常需要三联治疗方可治愈,而对于慢代谢型患者通常二联方案即可。同时CYP2C19也影响PPI与其它药物如氯吡格雷间的相互作用。