Effect of Genetic Differences in Omeprazole Metabolism on Cure Rates for Helicobacter pylori Infection and Peptic Ulcer

Methods

The study sample consisted of 62 Japanese patients with gastric ulcer (n = 33) or duodenal ulcer (n = 29). Sixty-one patients were male, and 1 was female; the mean age (±SD) was 46.5 ± 6.0 years. All patients had endoscopically proven ulcer and were positive for H. pylori on rapid urease testing, culture, and histologic examination.

For the treatment of ulcer, 20 mg of omeprazole was administered once daily after breakfast for 8 weeks to patients with gastric ulcer and for 6 weeks to patients with duodenal ulcer. In addition, 500 mg of amoxicillin was given four times daily to all patients for the first 2 weeks of omeprazole treatment. Patient adherence to therapy and occurrence of side effects were assessed by interview. Gastroduodenoscopy and determination of H. pylori infection were done before and 1 month after treatment. Endoscopists were blinded to patients' treatment status and genotypes. Written informed consent was obtained from each patient before the study began, and our protocol was approved by the Human Institutional Review Board of Hamamatsu University School of Medicine.

During gastroduodenoscopy, we performed routine inspection of the upper gastrointestinal tract and obtained gastric juice and several biopsy specimens from both the antrum and the corpus of the greater curvature for rapid urease testing, bacteriologic culture, histologic examination, and polymerase chain reaction (PCR), as reported elsewhere [13]. All patients also had ¹³C-urea breath testing [13].

Cure of H. pylori infection was determined according to the results of culture, histologic examination, rapid urease testing, ¹³C-urea breath testing, and PCR. Failure to cure H. pylori infection was defined as a positive result on any of these tests.

Genotyping procedures identifying CYP2C19 wild-type gene and the two mutated alleles, CYP2C19_m1 in exon 5 and CYP2C19_m2 in exon 4, were performed by a PCR restriction fragment length polymorphism method, as described by de Morais and colleagues [14, 15], with minor modifications as reported by Kubota and coworkers [16].

Numeric data are given as the mean ±SD. Statistical differences in mean age, body weight, ratios of gastric ulcer to duodenal ulcer, and cure rates for H. pylori infection among the genotype groups were determined by using one-way analysis of variance and the Fisher exact test. Calculations were done with SAS software (SAS Institute, Cary, North Carolina). All P values were two-sided; P values less than 0.05 were considered statistically significant.

Results

No clinically undesirable signs or symptoms attributable to the dual therapy used in our study were recognized during the study period. All patients completed the study according to the protocol. Adherence to the prescribed medication regimen was 100% in 43 patients, about 90% in 18 patients, and about 75% in 1 patient. Helicobacter pylori was eradicated in 58%, 33%, and 100% of patients whose adherence was 100%, 90%, and 75%, respectively.

Five different allelic patterns were noted in the 62 patients. Of the 62 patients, 28 were homozygous for the wild-type alleles (rapid-metabolizer group) in both exon 5 and exon 4 (wild-type/wild-type), 21 were heterozygous for the CYP2C19 (_m1) mutation without the CYP2C19_m2 mutation (wild-type/CYP2C19_m1), 4 were heterozygous for the CYP2C19_m2 mutation without CYP2C19_m1 mutation (wild-type/CYP2C19_m2), 4 were heterozygous for the CYP2C19_m1 mutation and the CYP2C19_m2 mutation (CYP2C19_m1/CYP2C19m2), and 5 were homozygous for the CYP2C19_m1 mutation without the CYP2C19_m2 mutation (CYP2C19_m1/CYP2C19m1). Patients were arbitrarily classified into three genotype groups as follows: Group 1 was the nonmutation group (wild-type/wild-type) (n = 28), group 2 was the one-mutation group (wild-type/CYP2C19_m1 or wild-type/CYP2C19_m2) (n = 25), and group 3 was the two-mutation group (CYP2C19_m1/CYP2C19m1 or CYP2C19_m1/CYP2C19m2) (n = 9) (Table 1). The CYP2C19 phenotypes of groups 1, 2, and 3 correspond to the rapid-extensive metabolizer, intermediate-extensive metabolizer, and poor-metabolizer phenotypes of CYP2C19, respectively [11, 16]. The relative mean area under the curve for omeprazole in the rapid-, intermediate-, and poor-metabolizer groups has been reported to be 1:3.7:20 [11].

Helicobacter pylori infection was cured in 32 of the 62 patients (51.6% [95% CI, 38.5% to 64.6%]). The cure rates of H. pylori infection for the three genotype groups are shown in Table 2. The cure rate was highest in group 3, intermediate in group 2, and lowest in group 1. Ulcer healing was achieved in 27 of the 33 patients with gastric ulcer and 24 of the 29 patients with duodenal ulcer. In patients in whom H. pylori infection was cured, all ulcer lesions were healed at follow-up endoscopic examination. Ulcer healing rates for patients with gastric ulcer in groups 1, 2, and 3 were 58.8% (CI, 27.7% to 84.8%) (7 of 12 patients), 92.9% (CI, 75.3% to 99.8%) (13 of 14 patients), and 100.0% (59.0% to 100.0%) (7 of 7 patients), respectively. Ulcer healing rates for patients with duodenal ulcer were 81.3% (CI, 54.4% to 96.0%) (13 of 16 patients), 81.8% (48.2% to 97.7%) (9 of 11 patients), and 100.0% (15.8% to 100.0%) (2 of 2 patients), respectively.

Discussion

Our study shows that rates of cure of H. pylori infection with omeprazole, 20 mg/d for 6 or 8 weeks, and amoxicillin, 2000 mg/d for 2 weeks, depend on CYP2C19 genotype patterns. In the poor-metabolizer group (patients with CYP2C19_m1/CYP2C19m1 or CYP2C19_m1/CYP2C19m2), dual therapy with 20 mg of omeprazole and 2000 mg of amoxicillin for 2 weeks seems to be fully effective in curing H. pylori infection. Thus, it may be unnecessary to prescribe additional drugs, such as clarithromycin or metronidazole, for these patients.

We suggest several reasons why dual treatment may yield greater success in curing H. pylori infection in patients with the poor-metabolizer genotype (group 3) than in those with the extensive-metabolizer genotypes (groups 1 and 2). First, because the metabolic disposition of omeprazole co-segregates with genetically determined CYP2C19 enzyme activity, the plasma concentration-time curve of omeprazole (that is, the systemic availability of the drug in circulation) is markedly increased in persons with the poor-metabolizer phenotype or genotype of CYP2C19 [10-12]. Consequently, the duration of high intragastric pH levels would be longer in patients with the poor-metabolizer genotype than in those with the extensive-metabolizer genotypes. Second, because amoxicillin is unstable and its antibacterial activity is decreased under low pH conditions, increasing the intragastric pH to neutral levels by using acid-inhibitory agents such as omeprazole may increase the availability of active antibiotic [17]. Third, omeprazole has been reported to increase amoxicillin concentrations in gastric juice [18]. Accordingly, when omeprazole and amoxicillin are coadministered, amoxicillin would be more stable and would be available in the stomach for longer periods at levels exceeding its minimum inhibitory concentration in patients with the poor-metabolizer genotype. Finally, omeprazole itself has been reported to have anti-H. pylori activity [19], which is presumably enhanced in patients with the poor-metabolizer genotype. Thus, both the higher cure rates for H. pylori infection and an increased acid-inhibitory effect of omeprazole may contribute to the excellent ulcer healing rates seen in patients with the poor-metabolizer genotype of CYP2C19 who have either gastric ulcer or duodenal ulcer disease.

Substantial ethnic differences have been reported in the incidence of the poor-metabolizer genotype of CYP2C19. The frequency of this genotype is much lower (3% to 5%) in white U.S. or European populations than in Japanese persons (18% to 23%) [9-11]. Thus, it seems reasonable that dual therapy with omeprazole (20 to 40 mg/d) and amoxicillin (2000 mg/d) has generally not achieved adequate cure rates for H. pylori infection and ulcer disease in white persons [4, 6]. However, Bayerdorffer and associates [20] reported that dual therapy with high dosages of omeprazole (40 mg three times daily) and amoxicillin (750 mg three times daily) could achieve a cure rate of 91% in white persons, even though most of the patients probably had extensive-metabolizer genotypes. A dose of at least 120 mg of omeprazole in dual therapy may therefore be required to achieve a sufficiently high cure rate of H. pylori infection in persons with extensive-metabolizer genotypes.

Our results must be interpreted within the context of our study's limitations. First, we did not measure plasma omeprazole levels and were therefore unable to directly correlate H. pylori infection and ulcer cure rates with plasma drug availability. Second, our sample size was small. Our findings must be considered preliminary; further study is required in larger groups of patients and should include measurement of plasma omeprazole concentrations. The additional costs of establishing the genotypic status of patients through direct genetic testing and of using larger doses of omeprazole in dual therapy in persons with extensive-metabolizer genotypes may be offset by the reduced costs and toxicity associated with avoidance of a second antibiotic, but the clinical usefulness and cost-effectiveness of genotyping as a clinical tool in the management of H. pylori-associated gastrointestinal disease remain to be determined.

Drs. Ohashi and Kosuge: Department of Clinical Pharmacology, Hamamatsu University School of Medicine, 3600, Handa-cho, Hamamatsu 431-3192, Japan.

Dr. Kamata: Hamamatsu Health Service Center, Honda Motor Co., Ltd., Hamamatsu Factory, 1-13-1, Aoihigashi, Hamamatsu 433-8501, Japan.

Dr. Kawasaki: Second Department of Medicine, Hamamatsu University School of Medicine, 3600, Handa-cho, Hamamatsu 431-3192, Japan.

Dr. Kubota: Research Testing Department, SRL, Inc., Hachioji Laboratory 153, Komiya-cho, Hachioji, Tokyo 192-8535, Japan.

Dr. Ishizaki: Department of Pharmacology and Therapeutics, Graduate School of Clinical Pharmacy, Kumamoto University, Oe-Honmachi, 5-1, Kumamoto 862-0973, Japan.