CYP2C19 genotype-related efficacy of omeprazole for the treatment of infection caused by Helicobacter pylori

OBJECTIVES: Omeprazole is used for the treatment of infection caused by Helicobacter pylori, and it is metabolized by the polymorphic cytochrome P4502C19 (CYP2C19). We have found that the anti-H pylori efficacy by the combination of omeprazole and antibiotics is related to the CYP2C19 genotype. METHODS: One hundred eight patients with cultured H pylori-positive gastritis or peptic ulcer were treated with three regimens: quadruple treatment without proton pump inhibitors (n = 25), dual treatment with omeprazole and amoxicillin (INN, amoxicilline) (n = 26), and triple treatment with omeprazole, amoxicillin, and clarithromycin (n = 57). The CYP2C19 genotype was determined by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method and the assessment of the eradication of H pylori was based on all negative examinations, including culture, histology, and 13C-urea breath test. RESULTS: The eradication rates for the extensive metabolizers were 50% and 86% for the dual and triple treatments, respectively. In contrast, all of the poor metabolizers treated with omeprazole and antibiotics (n = 15) showed an eradication of H pylori. CONCLUSION: The anti-H pylori effect of dual treatment is highly efficient for CYP2C19 poor metabolizers, which suggests that clarithromycin is not necessary as a first line of therapy for this type of patients. Genotyping can provide a choice for the optimal regimen based on individual CYP2C19 genotype.     

CYP2C10基因多态性对奥美拉唑治疗十二指肠溃疡的影响

目的 探讨奥美拉唑治疗十二指肠溃疡合并幽门螺旋菌感染的疗效及其与CYP2C19基因多态性的关系.方法 应用奥美拉唑+阿莫西林+克拉霉素三联用药1周后单用奥美拉唑抑酸3周的方案治疗65例经胃镜证实的十二指肠溃疡合并幽门螺旋菌( Hpylori)感染患者.记录治疗前和用药后症状的变化,并于治疗结束时复查胃镜.患者CYP2C19的基因型检测采用聚合酶链式反应-限制性片段长度多态性(PCR-RFLP)分析方法.结果 65例十二指肠溃疡患者中,24例为纯合子强代谢者,31例为杂合子强代谢者,10例为弱代谢者.纯合子强代谢组、杂合子强代谢组和弱代谢组有效率分别为75.0％、90.3％和100％,纯合子强代谢组的治愈率显著低于弱代谢组(P＜0.05).弱代谢型组患者的Hpylori清除率显著高于纯合子强代谢型和杂合子强代谢型(P＜0.05).结论 CYP2C19基因多态性与奥美拉唑治疗十二指肠溃疡合并幽门螺旋菌感染的疗效密切相关.CYP2C19基因分型检测是临床治疗酸相关性疾病中的一个重要的工具.     

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.     

Acid-suppressive effects of rabeprazole, omeprazole, and lansoprazole at reduced and standard doses: a crossover comparative study in homozygous extensive metabolizers of cytochrome P450 2C19

BACKGROUND AND OBJECTIVES: To improve clinical outcomes of the initial therapy for gastroesophageal reflux disease, intragastric pH should be above 4.0 for more than 20 hours a day (83.3%) and nocturnal gastric acid breakthrough, defined as 60 continuous minutes of intragastric pH below 4.0 at night, should be inhibited. A "step-down" therapy sometimes fails because of insufficient acid suppression. Therefore we compared the acid-suppressive effects of proton pump inhibitors. METHODS: This was a prospective, randomized, open-label, 8-way crossover study. In 9 healthy Helicobacter pylori-negative cytochrome P450 (CYP) 2C19 homozygous extensive metabolizers, intragastric pH was measured for 24 hours on day 7 of treatment with rabeprazole, omeprazole, and lansoprazole orally administered once daily at reduced and standard doses. RESULTS: Compared with baseline data (7% [range, 5%-20%]), the median values of the 24-hour percent of time that intragastric pH was above 4.0 significantly increased but did not exceed 83.3% under any of the 7 regimens, which were as follows: 10 mg rabeprazole (51% [range, 28%-78%], P < .01), 20 mg rabeprazole (59% [range, 36%-83%], P < .01), 10 mg omeprazole (26% [range, 4%-33%], P < .05), 20 mg omeprazole (48% [range, 31%-73%], P < .01), 40 mg omeprazole (62% [range, 47%-87%], P < .01), 15 mg lansoprazole (34% [range, 5%-51%], P < .05), and 30 mg lansoprazole (56% [range, 20%-76%], P < .05). Significant differences were observed among 10, 20, and 40 mg omeprazole (10 mg versus 20 mg, P < .01; 10 mg versus 40 mg, P < .01; and 20 mg versus 40 mg, P < .05) and between 15 and 30 mg lansoprazole (P < .01), whereas no significant difference was observed between 10 and 20 mg rabeprazole. Nocturnal gastric acid breakthrough was observed under all regimens. CONCLUSIONS: Rabeprazole, omeprazole, and lansoprazole, given once daily at standard doses, cannot be expected to achieve ideal acid suppression for the initial therapy for gastroesophageal reflux disease in Helicobacter-negative CYP2C19 homozygous extensive metabolizers. Rabeprazole 10 mg may be appropriate for step-down therapy.     

Relationship between the birth cohort pattern of Helicobacter pylori infection and the epidemiology of duodenal ulcer

BACKGROUND: Helicobacter-pylori-related duodenal ulcer (DU) is an important cause of dyspepsia. AIM: To determine the relationship between the pattern of H. pylori infection and the epidemiology of duodenal ulcer in a single population. DESIGN: Prospective two-part study of (i) patients with DU referred for endoscopy because of dyspepsia, and (ii) the incidence of H. pylori infection in the general population of the same area. METHODS: Details of 533 DU patients were recorded, and related to the pattern of H. pylori infection among 10 537 adults in the same community, determined by the (13)C-urea breath test. RESULTS: In patients with DU, birth year was more important than age in determining the rate of presentation for endoscopy (the 'birth cohort' effect). H. pylori infection showed a similar birth cohort effect, and the prevalence decreased steadily in those born in successive years, from 28.8% in the 1930s to 3.5% in the 1970s. The proportion of dyspeptic patients who had duodenal ulcers also fell progressively, from 22.2% in 1979 to 5.7% in 1998. H. pylori prevalence and duodenal ulcer incidence were closely correlated at all ages. DISCUSSION: Duodenal ulcer prevalence (as judged by the rate of referral of duodenal ulcer patients for endoscopy) is determined principally by the distribution of H. pylori infection in the local population. The birth cohort effect seen in adult duodenal ulcer patients reflects the acquisition of H. pylori in childhood. In Bristol, H. pylori prevalence and duodenal ulcer incidence are both declining to very low levels.     

The role and treatment of Helicobacter pylori infection in peptic ulcer disease: a review of the relationship between Helicobacter pylori infection and peptic ulcer disease

The role of Helicobacter pylori in the progress of peptic ulcer disease is reviewed. In particular, the relationship between H. pylori infection and relapse rate is discussed, including an overview of current theories regarding the mechanism of tissue damage induced by the organism. The relative merits of the recommended drug therapies are outlined, with emphasis on their effectiveness in removing H. pylori from the gastrointestinal tract, the risks of the development of resistant strains of the organism, the adverse effects of the therapies and the approaches that are likely to be adopted in the future.     

Stereospecific analysis of omeprazole supports artemisinin as a potent inducer of CYP2C19

The purpose of the study was to determine the enantiomer pharmacokinetics of omeprazole and 5-hydroxy-omeprazole before and after administration of the antimalarial artemisinin to confirm artemisinin's ability to induce CYP2C19. Nine healthy male Vietnamese subjects were given a single 20 mg dose of omeprazole orally 1 week before (day - 7) artemisinin administration. Artemisinin was then given orally (500 mg) for 7 days (days 1-7). On days 1 and 7, a single 20 mg dose of omeprazole was coadministered with artemisinin. After a washout period of 6 days, a single 20 mg dose of omeprazole was again administered together with a single 500 mg of artemisinin (day 14). Stereoselective pharmacokinetics of omeprazole and 5-hydroxyomeprazole was determined on days of omeprazole administration. Seven days of artemisinin administration significantly decreased the AUC of both omeprazole enantiomers (day 7), compared with day 1 (P < 0.001). All values were normalized after the washout period. Artemisinin increased the AUC ratio of R-5-hydroxyomeprazole/R-omeprazole significantly (P < 0.01) on day 7. The AUC ratio of omeprazole sulphone/S-omeprazole did not differ between study days. Artemisinin decreased the AUC of S-omeprazole to the same extent as that of R-omeprazole in extensive CYP2C19 metabolizers. suggesting that artemisinin induces a different enzyme in addition to CYP2C19. These results support and strengthen earlier findings that artemisinin induces CYP2C19 as well as at least one enzyme other than CYP3A4.     

CYP2C19 haplotypes in Koreans as a marker of enzyme activity evaluated with omeprazole

Background and objective:  CYP2C19 is clinically important in Korea because of the relatively high incidence of poor metabolizers in the population. To fully understand the genetic mechanism of the CYP2C19 defect in poor metabolizers, all variants need to be studied simultaneously. The aim of this study was to investigate the usefulness of CYP2C19 haplotypes as a marker of CYP2C19 enzyme activity in Koreans.
Methods:  We analysed the single nucleotide polymorphisms and haplotypes of the CYP2C19 gene in 150 healthy Koreans and found three major (frequency > 0·1) haplotypes (H1, H2 and H3). One oral dose of 40 mg omeprazole (Losec^®) was administered to 30 subjects grouped as H1/H1, H2/H2, H1/H2, H1/H3 and H2/H3. The pharmacokinetics of omeprazole and its metabolites, 5-hydroxyomeprazole and omeprazole sulphone, in those groups was analysed.
Results and discussion:  The area under the plasma concentration–time curve (AUC_0→∞) and elimination half-life ( T _1/2) of omeprazole were significantly greater in the H2/H2 and H2/H3 groups than in the H1/H1 group ( P  <   0·05), whereas the metabolic ratios of omeprazole to 5-hydroxyomeprazole were also markedly higher.
Conclusion:  Although a specific SNP of CYP2C19 may be predictive of enzyme activity, haplotyping is more reliable for identifying poor metabolizers in populations with variant alleles other than CYP2C19*2 and *3 alleles.     

Enantioselective disposition of lansoprazole in extensive and poor metabolizers of CYP2C19

OBJECTIVE: To evaluate the enantioselective disposition of lansoprazole in relation to the genetic polymorphism of CYP2C19. METHODS: A single oral dose of racemic lansoprazole (30 mg) was administered to 6 extensive metabolizers and 6 poor metabolizers whose genotypes were determined by use of polymerase chain reaction-restriction fragment length polymorphism. The pharmacokinetic parameters were estimated from the plasma concentrations of lansoprazole racemate, its enantiomers, and metabolites, which were measured for 24 hours after drug administration. The unbound fraction of lansoprazole enantiomers was determined by means of ultrafiltration of fresh human serum spiked with racemic lansoprazole. RESULTS: The plasma concentrations of R(+)-lansoprazole were consistently higher than those of the S(-)-enantiomer in both extensive and poor metabolizers of CYP2C19, and the mean area under the plasma concentration-time curve of the (+)- and (-)-enantiomers showed 4.3- and 5.8-fold differences between poor and extensive metabolizers, respectively. The (+)/(-) ratios of lansoprazole clearance were not significantly different between poor and extensive metabolizers (0.19 +/- 0.07 and 0.05 +/- 0.08, respectively). The values for volume of distribution of the (-)-enantiomer were 3- and 10-fold greater, respectively, than those of the (+)-enantiomer in poor and extensive metabolizers, which was related to a 2-fold higher unbound fraction of the (-)-enantiomer. CONCLUSIONS: The effect of CYP2C19 genetic polymorphism on the enantioselective disposition of lansoprazole seems to be less significant than the effect on omeprazole and pantoprazole. The disposition of lansoprazole enantiomers appears to be influenced by enantioselective protein binding and by enantioselective metabolism of lansoprazole.     

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.     

Assessment of CYP2C19 genetic polymorphisms in a Korean population using a simultaneous multiplex pyrosequencing method to simultaneously detect the CYP2C19*2, CYP2C19*3, and CYP2C19*17 alleles

Background and objective: CYP2C19 is a drug‐metabolizing enzyme showing various genetic polymorphisms that may cause marked interindividual and interethnic variability in the disposition of its substrates. We assessed CYP2C19 genetic polymorphisms in a Korean population using a newly developed multiplex pyrosequencing method. Method: A multiplex pyrosequencing method to simultaneously detect CYP2C19*2, *3, and *17 alleles was designed. We established the frequency of these CYP2C19 alleles in 271 Korean subjects using the multiplex pyrosequencing method. Results: The results showed 100% concordance between single and multiplex pyrosequencing methods. We also validated the polymorphisms identified by pyrosequencing with direct sequencing method. The allele frequencies of CYP2C19*2, CYP2C19*3, and CYP2C19*17 were 0·284, 0·101 and 0·015 respectively. These frequencies are similar to that reported for other Asian populations including Japanese and Chinese but different from that of Caucasians and Africans. Conclusions: The multiplex pyrosequencing method to detect CYP2C19*2, CYP2C19*3, and CYP2C19*17 concurrently, seems to be a rapid and reliable genotyping method for the detection of important CYP2C19 genetic polymorphisms. Similar to studies conducted on other Asian populations, this study reported that in the Korean population tested, the CYP2C19*2 and CYP2C19*3 alleles were relatively frequently found, whereas the frequency of CYP2C19*17 was very low.     

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.     

Helicobacter pylori infection in a pediatric population: in vitro susceptibilities to omeprazole and eight antimicrobial agents.

The in vitro activities of omeprazole and eight antimicrobial agents against 18 clinical strains of Helicobacter pylori isolated from a pediatric population were determined by an agar dilution method. Ampicillin and erythromycin were the most active agents in vitro. All strains were susceptible to azithromycin, ciprofloxacin, doxycycline, metronidazole, and tinidazole. One isolate demonstrated resistance to cefixime (MIC, greater than or equal to 4 micrograms/ml). H. pylori was inhibited by the proton pump inhibitor omeprazole.     

LncRNA H19和miR-625-5p在消化性溃疡合并幽门螺杆菌感染患儿血清中的表达及意义

摘要:目的分析 长链非编码RNA( LncRNA) H19和微小RNA-625-5p( miR-625-5p)在消化性溃疡(PU)合并幽门螺杆菌(HP)感染患儿血清中的表达水平及意义。方法选取2021 年2月至2023年2月在泉州市儿童医院治疗的160例PU患儿,其中90例患儿合并HP感染(阳性组),70例未合并HP感染(阴性组),另收集同期160例体检健康儿童为健康人对照组。采用实时荧光定量PCR(qRT-PCR)检测各组LncRNA H19和miR-625-5p的相对表达水平;Pearson法分析PU合并HP感染患儿LncRNA H19和miR-625-5p的相关性; Logistice 回归分析LncRNA H19、miR-625-5p与PU患儿HP感染的关联;ROC曲线分析LncRNA H19和miR-625-5p表达对PU患儿HP感染的诊断价值。结果与健康人对照组相比,HP阴性组、阳性组PU患儿血清LncRNA H19水平依次显著升高( P<0.05) , miR-625-5p水平依次显著降低(P<0.05);与HP感染I型相比,HP感染II型PU患儿血清LncRNA H19水平显著降低(P<0.05) ,miR-625-5p水平显著升高( P<0.05) ;LncRNA H19与miR-625-5p间存在结合位点,且PU合并HP感染患儿血清LncRNA H19与miR-625-5p水平呈显著负相关(r=-0.536,P<0.05)。Logstic 回归分析发现,LncRNA H19是影响PU患儿HP感染的危险因素( P<0.05), miR-625-5p是PU患儿HP感染的保护因素(P<0.05);LncRNA H19、miR-625-5p诊断PU患儿HP感染的ROC曲线下面积( AUCROC)分别为0.870和0.895,二者联合诊断的AUCROC为0.935,优于其各自单独诊断(Zz者联合1neEVA m9 = 1.991 ,P=0.023 ;-_w_-25.5= 1.707,P=0.044)。结论PU 合并HP感染患儿血清LncRNA H19水平升高, miR-625-5p水平降低,二者对PU合并HP感染具有一定的诊断价值。     

老年患者细胞色素P4502C19基因多态性与兰索拉唑三联疗法根除幽门螺杆菌疗效的关系

目的：研究老年患者P4502C19基因多态性与以兰索拉唑为基础的三联1周疗法根除幽门螺杆菌疗效的关系。方法：选择125例诊断为幽门螺杆菌阳性的老年患者,同时选择105例年轻的幽门螺杆菌阳性患者为对照组,给予以兰索拉唑为基础的根除幽门螺杆菌治疗,运用AS-PCR方法检测cyp2C19的基因型,根据等位基因功能的缺失,分析CYP2C19基因型与幽门螺杆菌的除菌效果的关系。结果：在这125例老年患者中,检测到纯合子快代谢型,杂合子快代谢型以及慢代谢型,幽门螺杆菌根除率分别为85．29％,76％,89．39％。三者两两比较,差异无显著性（P＞0．05）。实验组与对照组的根除率两两比较差异无显著性（P＞0．05）。结论：老年患者CYP2C19基因多态性与以兰索拉唑为基础的三联疗法HP的根除率无相关性。