Effect of genotypic differences in CYP2C19 on cure rates for Helicobacter pylori infection by triple therapy with a proton pump inhibitor, amoxicillin, and clarithromycin

BACKGROUND: Proton pump inhibitors such as omeprazole and lansoprazole are mainly metabolized by CYP2C19 in the liver. The therapeutic effects of proton pump inhibitors are assumed to depend on CYP2C19 genotype status. OBJECTIVE: We investigated whether CYP2C19 genotype status was related to eradication rates of H pylori by triple proton pump inhibitor-clarithromycin-amoxicillin (INN, amoxicilline) therapy and attempted to establish a strategy for treatment after failure to eradicate H pylori. METHODS: A total of 261 patients infected with H pylori completed initial treatment with 20 mg of omeprazole or 30 mg of lansoprazole twice a day, 200 mg of clarithromycin three times a day, and 500 mg of amoxicillin three times a day for 1 week. CYP2C19 genotypes of patients were determined with polymerase chain reaction-restriction fragment length polymorphism analysis. Patients without eradication after initial treatment were retreated with 30 mg of lansoprazole four times daily and 500 mg of amoxicillin four times daily for 2 weeks. RESULTS: Eradication rates for H pylori were 72.7% (95% confidence interval, 64.4%-81.8%), 92.1% (confidence interval, 86.4%-97.3%), and 97.8% (confidence interval, 88.5%-99.9%) in the homozygous extensive, heterozygous extensive, and poor metabolizer groups, respectively. Thirty-four of 35 patients without eradication had an extensive metabolizer genotype of CYP2C19. Nineteen of those patients were infected with clarithromycin-resistant strains of H pylori. However, there were no amoxicillin-resistant strains of H pylori. Re-treatment of H pylori infection with dual high-dose lansoprazole-amoxicillin therapy succeeded in 30 of 31 patients with extensive metabolizer genotype of CYP2C19. CONCLUSION: The majority of patients without initial eradication of H pylori had an extensive metabolizer CYP2C19 genotype but were successfully re-treated with high doses of lansoprazole and an antibiotic to which H pylori was sensitive, such as amoxicillin, even when the patients were infected with clarithromycin-resistant strains of H pylori.     

Effect of high-dose lansoprazole on intragastic pH in subjects who are homozygous extensive metabolizers of cytochrome P4502C19.

BACKGROUNDS AND AIM: Lansoprazole is mainly metabolized by cytochrome P4502C19 (CYP2C19) in the liver. The effect of lansoprazole is assumed to be insufficient in subjects who are homozygous extensive metabolizers of CYP2C19. This study aimed to examine whether the CYP2C19 genotype status affected the acid-inhibitory effects of lansoprazole and to develop a strategy to overcome this pharmacogenetic problem. METHODS: Eighteen Helicobacter pylori-negative healthy volunteers, whose CYP2C19 genotypic status had been assessed, participated in the study. They consisted of 7 subjects who were homozygous extensive metabolizers, 7 subjects who were heterozygous extensive metabolizers, and 4 subjects who were poor metabolizers of CYP2C19, who took a placebo or lansoprazole 30 mg once daily in the morning for 8 days. On day 8 of dosing, 24-hour intragastric pH values were recorded. Five of the homozygous extensive metabolizer subjects underwent the 24-hour intragastric pH monitoring on day 8 of dosing of lansoprazole 30 mg 4 times daily. RESULTS: When lansoprazole 30 mg was given once daily, the mean 24-hour intragastric pH values in the subjects who were homozygous extensive metabolizers, heterozygous extensive metabolizers, and poor metabolizers were 4.5, 4.9, and 5.5, respectively (P <.005). On day 8 of dosing of lansoprazole 30 mg 4 times daily in subjects who were homozygous extensive metabolizers, the mean 24-hour intragastric pH value was 7.4. CONCLUSION: The effect of lansoprazole on intragastric pH depended significantly on CYP2C19 genotype status. Complete acid inhibition could be achieved by the frequent administration of lansoprazole (eg, 30 mg 4 times daily) in subjects who were homozygous extensive metabolizers. A genotyping test of CYP2C19 status appears useful for prescribing an optimal dosing scheme of lansoprazole.     

Progress of tailor-made treatment of peptic ulcer]

We previously reported that a comparative pharmacokinetic study with each PPI was designed as an open, randomized, and crossover study of 18 Japanese healthy volunteers who were classified into the homozygous, heterozygous extensive metabolizer and the poor metabolizer based on the CYP2C19 genotype. With at least 1 week washout period between treatments. Plasma concentrations of PPIs and their metabolites were monitored until 12 h after medication. Pharmacokinetic profiles of omeprazole and lansoprazole were well correlated with the CYP2C19 genotype. The heterozygous extensive metabolizer was slightly different from the homozygote, but there was no statistically significant difference. The CYP2C19 genotype dependence found for lansoprazole was not obvious compared with omeprazole. As for rabeprazole, the pharmacokinetic profile was independent of the CYP2C19 genotype. CYP2C19 genotyping can provide a new strategy to choose an optimal regimen, and this genotyping is especially useful for Japanese, as the frequency of poor metabolizers is five times greater than that found among Caucasians.     

荧光PCR检测CYP2C19基因分型与氯吡格雷临床疗效的相关性研究

目的通过分析CYP2C19基因型与ADP抑制率之间的关系,探讨CYP2C19基因分型与氯吡格雷抗凝治疗效果的关系。方法选取急性冠脉综合征（ACS）并成功接受经皮冠状动脉介入治疗术（PCI）的患者55例,收集患者EDTA抗凝静脉血提取血液基因组DNA,用实时荧光PCR方法分析CYP2C19基因型,测定每名患者ADP抑制率,用统计学方法分析CYP2C19不同基因型患者ADP抑制率的差异。结果所有入组患者根据基因型不同分为快代谢组占49.09%（27/55）,中等代谢组占38.19%（21/55）,慢代谢组占12.73%（7/55）。三组ADP抑制率比较,两两相比差异均有统计学意义（P〈0.01）。结论 CYP2C19基因多态性与氯吡格雷抵抗存在关联,快代谢型患者PCI术后服用氯吡格雷疗效好于携带基因突变的患者,慢代谢型患者PCI术后服用氯吡格雷疗效差。     

Effects of clarithromycin on the metabolism of omeprazole in relation to CYP2C19 genotype status in humans.

BACKGROUND AND PURPOSE: A triple therapy with omeprazole, amoxicillin (INN, amoxicilline), and clarithromycin is widely used for the eradication of Helicobacter pylori. Omeprazole and clarithromycin are metabolized by CYP2C19 and CYP3A4. This study aimed to elucidate whether clarithromycin affects the metabolism of omeprazole. METHODS: After administration of placebo or 400 mg clarithromycin twice a day for 3 days, 20 mg omeprazole and placebo or 400 mg clarithromycin were administered to 21 healthy volunteers. Plasma concentrations of omeprazole and clarithromycin and their metabolites were determined before and 1, 2, 3, 5, 7, 10, and 24 hours after dosing. CYP2C19 genotype status was determined by a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. RESULTS: Subjects were classified into three groups on the basis of PCR-RFLP analyses for CYP2C19: homozygous extensive metabolizer group (n = 6), heterozygous extensive metabolizer group (n = 11), and poor metabolizer group (n = 4). Mean area under the plasma concentration-time curves from 0 to 24 hours (AUC) of omeprazole in the homozygous extensive metabolizer, heterozygous extensive metabolizer, and poor metabolizer groups were significantly increased by clarithromycin from 383.9 to 813.1, from 1001.9 to 2110.4, and from 5589.7 to 13098.6 ng x h/mL, respectively. There were significant differences in the mean AUC values of clarithromycin among the three groups. CONCLUSION: Clarithromycin inhibits the metabolism of omeprazole. Drug interaction between clarithromycin and omeprazole may underlie high eradication rates achieved by triple therapy with omeprazole, amoxicillin, and clarithromycin.     

Tailor-made medicine in Helicobacter pylori eradication therapy

Pharmacokinetic profiles of omeprazole and lansoprazole were well correlated with the CYP2C19 genotype. The heterozygous extensive metabolizer was slightly different from the homozygote, but there was no statistically significant difference. The CYP2C19 genotype dependence found for lansoprazole was not obvious compared with omeprazole. As for rabeprazole, the pharmacokinetic profile was independent of the CYP2C19 genotype. CYP2C19 genotyping can provide a new strategy to choose an optimal regimen, and this genotyping is especially useful for Japanese, as the frequency of poor metabolizers is five times greater than that found among Caucasians. However, we should be aware that the increase of antimicrobial-resistant strains of H. pylori may force us to examine antimicrobial susceptibility of all patients in order to achieve a more than 80% eradication rate at first-line therapy in the near future. We should also have proper knowledge of the influence of the CYP2C19 genetic polymorphism on treatment efficacy according to the variety of PPI and the combination with other drugs.     

Cure of refractory duodenal ulcer and infection caused by Helicobacter pylori by high doses of omeprazole and amoxicillin in a homozygous CYP2C19 extensive metabolizer patient

A 53-year old female patient with duodenal ulcer and Helicobacter pylori infection was treated three times with a proton pump inhibitor-based triple therapy, such as lansoprazole-clarithromycin-amoxicillin (INN, amoxicilline) and lansoprazole-minocycline-cefaclor. However, the H pylori infection was not cured. A culture test revealed that her infection was a clarithromycin-resistant but amoxicillin-sensitive strain of H pylori. Moreover, a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis revealed that she was a homozygous extensive metabolizer of cytochrome P450 (CYP) 2C19 (wt/wt). The usual dose of the proton pump inhibitor was therefore assumed to be insufficient for her and then she was treated with a high dose of omeprazole (120 mg/day) and amoxicillin (2,250 mg/day) for 2 weeks. The H pylori infection and the ulcer lesion were then cured. One of the factors associated with success or failure of cure of H pylori infection by the proton pump inhibitor-based triple therapy appeared to be CYP2C19 genotype status. Dual treatment with a sufficient dose of a proton pump inhibitor plus amoxicillin could cure H pylori infection even after the failure to cure H pylori infection by a usual proton pump inhibitor-based triple therapy in patients with the wt/wt homozygous extensive metabolizer genotype of CYP2C19.     

Esomeprazole-induced healing of gastroesophageal reflux disease is unrelated to the genotype of CYP2C19: evidence from clinical and pharmacokinetic data

BACKGROUND: The clinical outcome of acid-related disorders treated by proton pump inhibitors (PPIs) might be dependent on the polymorphically expressed cytochrome P450 (CYP) 2C19, which is involved in PPI metabolism. We tested whether esomeprazole-induced healing of gastroesophageal reflux disease (GERD) is related to CYP2C19 genotype. METHODS: Two hundred five patients with GERD (Los Angeles classification grade A or B) were included in a case-control study according to endoscopic outcome (healed versus unhealed group, matched for confounders) after treatment with 40 mg esomeprazole daily for 4 weeks. The frequency of CYP2C19 genotypes was determined as the primary outcome measure for both groups. In a second trial plasma levels of esomeprazole and corresponding CYP2C19 and CYP3A4 metabolites (5-hydroxyomeprazole and omeprazole sulfone) were monitored in 10 CYP2C19 wild-type patients with GERD after the first and last doses (day 7) of 40 mg esomeprazole daily to calculate metabolic ratios. RESULTS: CYP2C19 wild-type (n = 148) and heterozygous (n = 51) or homozygous variant (n = 6) patients did not differ with respect to baseline characteristics. The frequency distribution of CYP2C19 genotypes was not different between patients with complete (75/100) and incomplete (73/105) healing (P = .65). When a single esomeprazole dose and multiple dosing were compared, the low contribution of CYP2C19 to the elimination of esomeprazole decreased further by 50%. In contrast, the CYP3A4-dependent formation of omeprazole sulfone increased by 40%, and consequently, the metabolic ratio of omeprazole sulfone to 5-hydroxyomeprazole was elevated from 7.9 to 19.3 (P = .0004). CONCLUSION: In contrast to other PPIs, esomeprazole-induced healing of GERD is unrelated to the CYP2C19 genotype, which can be explained by the metabolic shift toward the CYP3A4-mediated pathway.     

广东东莞地区心血管疾病患者CYP2C19基因多态性分析

目的研究广东东莞地区心血管病患者CYP2C19基因的多态性分布。方法选取心内科心血管疾病患者1 662例,抽取外周血并提取基因组DNA,用PCR技术结合基因芯片技术检测患者的CYP2C19基因型。对年龄45岁和年龄≥45岁冠心病患者CYP2C19等位基因频率和代谢表型频率进行比较。结果在1 662例患者中,CYP2C19代谢型713例(42.90%),中间代谢型740例(44.52%),慢代谢209例(12.58%)。CYP2C19*1、CYP2C19*2、CYP2C19*3等位基因频率分别为65.16%、30.08%、4.75%。45岁组检出快代谢型104例(40.00%),中间代谢型104例(45.38%),慢代谢型38例(14.62%)。≥45岁冠心病组检出快代谢型609例(43.44%),中间代谢型622例(44.37%),慢代谢171例(12.20%)。45岁与≥45岁组各基因型的比例比较,差异无统计学意义(P0.05)。结论通过检测CYP2C19基因型确定患者遗传特征,可以评估其氯吡格雷抵抗风险,为患者制订个体化的抗血小板治疗方案。     

Influences of proinflammatory and anti-inflammatory cytokine polymorphisms on eradication rates of clarithromycin-sensitive strains of Helicobacter pylori by triple therapy

BACKGROUNDS AND AIMS: Polymorphisms of proinflammatory cytokines, such as interleukin (IL) 1beta and tumor necrosis factor (TNF) alpha, are associated with individual differences in gastric mucosal inflammation and acid inhibition in response to Helicobacter pylori infection. We investigated whether inflammation-related cytokine polymorphisms would influence the eradication rates of H pylori by a triple-therapy regimen. METHODS: Three hundred sixty patients infected with clarithromycin-sensitive strains of H pylori were genotyped for IL1B -511, IL1RN, TNFA -857/-863/-1,031, IL10 -1,082/-819/-592, and CYP2C19 and underwent triple therapy for 1 week with a proton pump inhibitor (20 mg omeprazole, 30 mg lansoprazole, or 10 mg rabeprazole) twice daily, 400 mg clarithromycin twice daily, and 750 mg amoxicillin (INN, amoxicilline) twice daily. The influences of the previously mentioned polymorphisms on the eradication rates were analyzed. RESULTS: The intention-to-treat-based total eradication rate was 83.6% (301/360). The logistic regression analysis revealed that polymorphisms of CYP2C19 and IL1B -511 were independently associated with the eradication rates, but other cytokine polymorphisms were not associated with these rates. The eradication rates in patients with IL1B -511 C/C, C/T, and T/T genotypes were 72.2% (70/97), 87.7% (164/187), and 88.2% (67/76), respectively (P = .0017). When patients were stratified by CYP2C19 genotype status, IL1B -511 genotype-dependent differences in eradication rates were observed in homozygous extensive metabolizers (EMs) but not in heterozygous EMs and poor metabolizers of CYP2C19. The eradication rate in homozygous EM patients with the IL1B -511 C/C genotype was quite low (51.1% [22/43]). CONCLUSIONS: IL1B -511 polymorphism, but not IL1RN, TNFA, or IL10 polymorphism, is one of the determinants of triple therapy for clarithromycin-sensitive strains of H pylori in CYP2C19 homozygous EMs.     

基于武汉地区PCI术后患者CYP2C19基因多态性指导氯吡格雷个体化用药的研究

目的 研究CYP2C19基因多态性,分析经皮冠状动脉介入治疗(PCI)术后氯吡格雷中、慢代谢患者个体化用药的疗效差异,为PCI术后患者个体化用药提供参考依据.方法 使用荧光定量PCR法测定该院328例PCI术后患者CYP2C19基因型,分析年龄、性别与CYP2C19基因多态性的关系及不同地区汉族冠心病患者代谢表型差异,...     

Pathogenesis and treatment of refractory gastroesophageal reflux disease in Japanese patients

Prevalence of refractory gastroesophageal reflux disease (GERD) defined as a patient who have persistent GERD symptoms during treatment with proton pump inhibitor (PPI) is rare in Japanese patinets. Pathogenesis of refractory GERD is associated with several factors including dysfunction of esophageal motility, presence of severe hiatal hernia, complication such as stricture and short esophagus, extensive metabolizer of CYP2C19 genotype, nocturnal gastric acid breakthrough, absence of H. pylori infection, or bile reflux. Examination by 24 hr pH monitoring is necessary to assess refractory GERD and if acid suppression is insufficient, treatment with double doses of PPIs or combination of PPI and H2 blocker is effective. However, most cases of refractory GERD are required surgical treatment. Endoscopic therapy might be useful for refractory GERD in future.     

冠心病患者CYP2C19基因多态性及临床不良事件发生与氯吡格雷抵抗的关系

目的通过分析经皮冠状动脉介入治疗(PCI)术后冠心病患者的CYP2C19基因型结果、临床相关危险因素和主要心血管不良事件发生情况与氯吡格雷抵抗的关系,探讨影响氯吡格雷抵抗发生、发展的因素,为临床治疗提供有效依据。方法收集2017年1月至2018年12月该院收治并进行过基因检测的346例冠心病患者资料,分析其CYP2C19基因型和代谢型分布特征,筛选出251例使用氯吡格雷的PCI术后冠心病患者,进行血小板聚集功能试验检测,根据血小板最大聚集率(MAR)分为氯吡格雷敏感组(MAR<50%)和氯吡格雷抵抗组(MAR≥50%)。利用荧光PCR法进行CYP2C19基因多态性检测,根据基因型结果分为快代谢型(*1/*1)、中代谢型(*1/*2、*1/*3)和慢代谢型(*2/*2、*2/*3、*3/*3)。比较氯吡格雷抵抗组与氯吡格雷敏感组不同代谢型的患者比例、相关危险因素情况及临床心血管不良事件发生情况。结果慢代谢型患者的MAR较中代谢型、快代谢型患者高,差异均有统计学意义(P<0.05)。入选的251例患者中,氯吡格雷抵抗组CYP2C19代谢型分别为快代谢型38例(34.5%)、中代谢型57例(51.8%)、慢代谢型15例(13.6%),氯吡格雷抵抗组与氯吡格雷敏感组在快代谢型中的患者比例差异有统计学意义(P<0.05)。氯吡格雷抵抗组的高血压患者比例(91.8%)与氯吡格雷敏感组(63.8%)比较,差异有统计学意义(P<0.05)。氯吡格雷抵抗组临床心血管不良事件发生率(94.5%)高于氯吡格雷敏感组(84.4%),差异有统计学意义(P <0.05)。结论CYP2C19基因突变和高血压可能是氯吡格雷抵抗发生的两个重要影响因素,并且氯吡格雷抵抗增加了PCI术后冠心病患者临床心血管不良事件发生的风险。     

CYP2C19基因多态性在江苏及其周边地区汉族人群的调查研究

目的探讨CYP2C19基因型在江苏及其周边地区汉族人群中基因多态性的分布。方法取81名汉族健康人的外周血,应用聚合酶链反应(PCR)-限制性片段长度多态性分析(RFLP)CYP2C19等位基因分型。结果在81名检测标本中,CYP2C19纯合子强代谢型、杂合子强代谢型和弱代谢型的发生率分别为38.3%、45.7%和16.0%。结论江苏及其周边地区汉族人群存在CYP2C19的基因多态性,其弱代谢型的发生率与中国汉族人总体发生率基本一致。     

Interluekin-1 beta genetic polymorphism influences the impact of cytochrome P 2C19 genotype on the cure rate of H. pylori eradication therapy

Genetic polymorphism of interleukin(IL)-1 beta is associated with differences in gastric acid suppression in response to H. pylori infection. Thus, the polymorphism might affect H. pylori eradication therapy since antibiotics used in treatment regimens may be acid-sensitive. We examined the impact of IL-1 beta genetic polymorphism on the cure rate of triple therapy for H. pylori in relation to cytochrome P(CYP)2C19 genotype. In the normal acid-secretion IL-1 beta genotype group, the cure rate among CYP2C19 poor metabolizers was significantly higher than among those in the CYP2C19 extensive metabolizer groups. IL-1 beta genetic polymorphism, although not an independent factor in treatment outcome, influences the impact of the CYP2C19 genotype on the cure rate of H. pylori eradication therapy.     

CYP2C19 polymorphism is a major predictor of treatment failure in white patients by use of lansoprazole-based quadruple therapy for eradication of Helicobacter pylori

OBJECTIVE: Proton pump inhibitors, metabolized by the polymorphic enzyme cytochrome P450 (CYP) 2C19, are essential drugs for Helicobacter pylori eradication. It was reported that patients with CYP2C19 wild type in Asia had lower eradication rates. This study tests the hypothesis that CYP2C19 wild type ( wt/wt ) in white patients is also associated with a higher probability of treatment failure. METHODS: This was a cohort study involving 131 H pylori -positive white (German) patients treated by quadruple therapy including lansoprazole (30 mg twice daily for 5 days). Eradication success, as well as lansoprazole trough steady-state serum concentrations, was determined according to different CYP2C19 genotypes. RESULTS: We found 3 homozygous variant patients (2.3%) ( mt/mt, CYP2C19*2/*2 ), 42 heterozygous patients (32.1%) ( wt/mt, CYP2C19*1/*2 ), and 86 wild-type individuals (65.6%). Significant differences in eradication success could be found between wt/wt patients (80.2%) versus combined mt/mt (100%) and wt/mt patients (97.8%) ( P <.01; odds ratio, 10.8 [confidence interval, 1.4-84]), which were associated with corresponding changes in the serum levels of lansoprazole (median, 753 ng/mL for mt/mt, 59 ng/mL for wt/mt, and 21 ng/mL for wt/wt; P <.001). Apart from antibiotic resistance, CYP2C19 polymorphism was the most important influencing factor for eradication success on multivariate analysis ( P <.0001). CONCLUSION: Eradication rates of H pylori highly depend on CYP2C19 in white patients if standard doses of lansoprazole (30 mg twice daily) are administered within a quadruple regimen. Because wt/wt individuals have lower eradication rates and lower serum concentrations of lansoprazole, these patients might benefit from a higher proton pump inhibitor dosage.     

Theophylline pharmacokinetics are not altered by lansoprazole in CYP2C19 poor metabolizers.

Lansoprazole is a potent gastric proton pump inhibitor that is metabolized by CYP2C19 but appears to induce the activity of hepatic microsomal CYP1A2 in a concentration-dependent manner. Because the inducing effect appears to be a dose-dependent phenomenon, it may be more important in poor metabolizers of CYP2C19 who have more than four times the area under the lansoprazole plasma concentration-time curve (AUC) and constitute 12% to 23% of Asian populations. Theophylline owes a significant portion of its metabolism to CYP1A2 and can cause gastric acid reflux that calls for concurrent use of proton pump inhibitors. We conducted a prospective, randomized, subject-blind, multicenter crossover study of the effect of multiple high-dose oral lansoprazole (30 mg twice a day for 7 days) on the pharmacokinetics of a single intravenous dose of theophylline (4.73 mg/kg) in healthy volunteers characterized for CYP2C19 genotype. The study compared the pharmacokinetics of lansoprazole and theophylline in five white extensive metabolizers, six Korean extensive metabolizers, and seven poor metabolizers of CYP2C19. The pharmacokinetics of lansoprazole were significantly different among groups; AUC values were 1.55+/-0.20 microg x h/mL in white extensive metabolizers, 7.01+/-0.72 microg x hr/mL in Korean extensive metabolizers, and 14.34+/-2.60 microg x h/mL in poor metabolizers (P < .001). The administration of lansoprazole did not change intravenous theophylline clearance compared with placebo in any group, and theophylline clearance exhibited no correlation with AUC of lansoprazole (rs = 0.12; P > .1). These data suggest that usual therapeutic doses of lansoprazole have no clinically significant influence on the clearance of theophylline, even in poor metabolizers of CYP2C19.     

Test of refractory gastroesophageal reflux disease

It should be considered that the causes of refractory gastroesophageal reflux disease (GERD) are multifactorial. Esophageal manometry study is useful when we make distinguish patients with esophageal motility disorders from those with refractory GERD. Endoscopic ultrasonography is also performed to observe the thickness of esophageal wall which represents the disturbance of esophageal motor function. Esophageal pH monitoring is useful to detect the acid clearance disturbance and phenomenon of nocturnal acid breakthrough. Both are occurred at night, and are recently considered to be responsible for refractory GERD. Catheter-free pH monitoring system, Bravo, makes it possible to measure esophageal pH under quite physiological conditions. Genotype of CYP2C19 is sometimes checked in patients with PPI resistance GERD. Intra-gastric pH with omeprazole and lansoprazole depends on patient's genotype of CYP2C19. Monitoring of 24-hour bilirubin, Bilitec, is also useful to detect duodeno-gastro-esophageal reflux.     

Effects of CYP2C19 genetic polymorphism on the pharmacokinetics and pharmacodynamics of omeprazole in Chinese people

BACKGROUND: To investigate whether the pharmacodynamics and pharmacokinetics of omeprazole (OPZ) are dependent of the CYP2C19 genotype status in Chinese people. METHODS: Eighteen healthy subjects were voluntary to participate in the study, whose CYP2C19 genotype status were determined by polymerase chain reaction-restriction fragment length polymorphism method. There were six homozygous extensive metabolizers, six heterozygous extensive metabolizers and six poor metabolizers (PMs). All subjects were Helicobacter pylori-negative, determined by serology method and (13)C-urea breath test. After d1 and d8 orally received OPZ 20 mg once daily in the morning, intragastric pH values were monitored for 24 h by Digitrapper pH. Meanwhile, blood samples were collected at various time-points until 24 h after administration. The serum concentrations of OPZ were measured by liquid chromatography. RESULTS: After single or repeated doses, the PMs showed a significantly higher mean area under the serum concentration-time curves (AUC) values than that observed in the homozygous extensive metabolizers or the heterozygous extensive metabolizers, with a relative ratio of 1.0 : 1.1 : 4.2 and 1.0 : 1.3 : 3.3 (homozygous extensive metabolizers:heterozygous extensive metabolizers:poor metabolizers), respectively. After a single dose of OPZ, significant differences in intragastric pH median, pH > 3 holding time and pH > 4 holding time were observed among the three groups. After repeated doses, the PMs showed a significantly higher intragastric pH values than that observed in the homozygous extensive metabolizers or the heterozygous extensive metabolizers. CONCLUSION: The pharmacodynamic effects of OPZ and its pharmacokinetics depend on the CYP2C19 genotype status in Chinese people.