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Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. SUBJECTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. References

Background:

CYP2C19 has an important role in the catabolism of several proton pump inhibitors. However, the relative contribution of CYP2C19-mediated metabolism varies among the different proton pump inhibitors.

Aim:

To determine the effect of CYP2C19 genotype status on intragastric pH during dosing with lansoprazole or rabeprazole.

Subjects and methods:

The subjects were 20 male volunteers without Helicobacter pylori infection. Their CYP2C19 genotype status was determined by a polymerase chain reaction-restriction fragment length polymorphism method. Twenty-four-hour monitoring of intragastric acidity was performed three times: once without medication, once on the last day of a 7-day course of rabeprazole, and once on the last day of a 7-day course of lansoprazole.

Results:

Subjects were divided into three groups on the basis of their CYP2C19 genotype status: homozygous extensive metabolizers (homo-EMs, n=7), heterozygous extensive metabolizers (hetero-EMs, n=9), and poor metabolizers (PMs, n=4). The median pH during rabeprazole administration was not influenced by CYP2C19 genotype. On the other hand, the median pH in PMs during lansoprazole dosing was higher than in homo-EMs and hetero-EMs. The percentage of time with pH < 4.0 had a similar tendency to that of median pH.

Conclusion:

CYP2C19 genotype status influences gastric acid suppression by lansoprazole, but not by rabeprazole.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. SUBJECTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. References

The therapeutic efficacy of drugs that suppress gastric acid secretion in the healing of peptic ulcers and gastro-oesophageal reflux disease (GERD) depends on the potency of acid suppression.1,2 The proton pump inhibitors, which cause potent and long-lasting inhibition of the terminal step in gastric acid secretion, are considered to be the most effective medical treatment for the management of patients with acid-related diseases.3, 4 However, interindividual variations in the suppressive effect of proton pump inhibitors on gastric acid secretion have been reported.5[6]–7Helicobacter pylori infection is reported to affect the acid suppressing effect of proton pump inhibitors and is regarded as one of the factors that cause interindividual variations in their effect.8[9][10][11]–12

Recently, it has also been found that CYP2C19, which is one of the isoenzymes of cytochrome P450 (CYP) in the liver and has important roles in the catabolism of proton pump inhibitors, has two genetically determined phenotypes: extensive metabolizers (EMs) and poor metabolizers (PMs).13[14][15][16]–17 Variation in phenotype affects the acid suppressing effects of omeprazole by changing its rate of catabolism.18 These two phenotypes of CYP2C19 can be determined by measuring urinary 4′-hydroxymephenytoin excretion or urinary S/R enantiomeric ratio after a single dose of racemic mephenytoin.19, 20 The phenotypic polymorphism of CYP2C19 can also be determined by ascertaining the presence or absence of single base pair mutations in exons 5 and 4 of the CYP2C19 gene. The mutation in exon 5 is termed CYP2C19m1 (m1) and that in exon 4 is termed CYP2C19m2 (m2).21, 22 According to a genotyping analysis, the PM phenotype consists of three genotypes (i.e. m1/m1, m2/m2, m1/m2), while the EM phenotype includes two genotypes, homozygous (i.e. wild type (wt)/wt) and heterozygous (i.e. wt/m1, wt/m2).23

Although CYP2C19 has an important role in their catabolism, the relative contribution of CYP2C19-mediated metabolism was reported to vary among the different proton pump inhibitors.13[14][15][16]–17 A study investigating the plasma concentrations of these proton pump inhibitors reported that the catabolism of lansoprazole and rabeprazole was less dependent on CYP2C19 than that of omeprazole.24 However, the influence of CYP2C19 genotype on intragastric pH during lansoprazole or rabeprazole administration has not yet been investigated. For clinical purposes, the most important information is not the effect of the CYP2C19 genotype on plasma concentrations of the proton pump inhibitors but the effect of CYP2C19 genotype on intragastric pH during proton pump inhibitor dosing.

Therefore, this study was designed to clarify the influence of CYP2C19 genotype on the potency of gastric acid suppression by repeated doses of lansoprazole or rabeprazole. For this purpose, a 24-h intragastric pH monitoring study was performed, both with and without proton pump inhibitor dosing.

SUBJECTS AND METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. SUBJECTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. References

Subjects

Thirty-six male Japanese volunteers who had no dyspeptic symptoms, no history of gastrointestinal or hepatobiliary diseases and who were not taking any medication on a regular basis were recruited for this study. A complete medical history was taken, a physical examination was performed, and fasting blood samples were collected from all subjects.

Before entry study, H. pylori infection was investigated by measuring serum H. pylori IgG antibodies with an enzyme-linked immunosorbent assay kit (IMMUNIS anti-PYLORI EIA; Institute of Immunology, Tokyo, Japan) and by the 13C-urea breath-test (UBT). Only individuals with negative serological test and negative UBT were considered to be free from H. pylori infection; the other individuals were diagnosed as positive for H. pylori infection. Sixteen volunteers were diagnosed as having H. pylori infection; consequently, the 20 volunteers (mean age 35.4 years, range 25–48 years) without H. pylori infection were employed for the following study.

CYP2C19 genotyping

CYP2C19 genotyping was performed by previously reported methods. Briefly, DNA was extracted from each subject’s peripheral blood with a commercially available kit (E.Z.N.A. Blood DNA Kit; Omega Biotek, Doraville, GA). Extracted genomic DNA was dissolved in distilled water (DNA solution). Genotyping procedures for identifying the CYP2C19 wild type (wt) gene and the two mutated alleles, m1 in exon 5 and m2 in exon 4, were performed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) with allele-specific primers, as described by de Morais et al.21, 22 The following origosynthesized primers were used in this study: m1F (5′-AATTACAACCAGAGCTTGGC-3′), m1R (5′-TATCACTTTCCATAAAAGCAAG-3′), m2F (5′-TATTATTATCTGTTAACTAATATGA-3′), and m2R (5′-ACTTCAGGGCTTGGTCAATA-3′). The 169-and 329-bp gene fragments were amplified by PCR, and their products were digested with restriction endonucleases (SmaI for m1 and BamHI for m2). The digested PCR products were analysed on 4% agarose gels and stained with ethidium bromide. Because CYP2C19m1 lacks a SmaI site and CYP2C19m2 lacks a BamHI site, the mutant alleles were resistant to endonuclease digestion. The subjects were divided into three groups by the existence of m1 and m2: homozygous extensive metabolizers (homo-EMs), wt/wt; heterozygous extensive metabolizers (hetero-EMs), wt/m1 and wt/m2; poor metabolizers (PMs), m1/m1, m1/m2, and m2/m2.

24-h pH monitoring

All subjects were examined three times by ambulatory pH monitoring for 24 h (from 17. 00 hours to the same time the following day): once without medication, once on the last day of a 7-day course of rabeprazole 20 mg/day, and once on the last day of a 7-day course of lansoprazole 30 mg/day. Rabeprazole or lansoprazole were administered daily for 7 days after breakfast. There was a wash-out period of 2 weeks between each period of proton pump inhibitor dosing. The three pH monitoring studies (the study without drug and the studies during treatment with rabeprazole or lansoprazole) were performed in a randomized order.

Ambulatory pH monitoring was performed with an antimony pH catheter (Zenetics Medical Inc, Salt Lake City, UT) placed on the gastric greater curvature of the middle body under fluoroscopic guidance. Calibration was performed before each recording according to the manufacturer’s recommendations. The pH values were recorded on a Digitrapper Mark III (Synectics Medical Inc, Stockholm, Sweden). After recording, digital values were transferred to a personal computer for processing and editing using a commercially available software program (Esophagogram; Gastrosoft, Stockholm, Sweden). Examiners and analysers of the pH monitoring test were blinded to the CYP2C19 genotype status of the subjects.

All ambulatory pH monitoring in this study was performed with subjects receiving a standard diet consisting of: total calories = 1359 kcal; protein, 24 g; lipids, 18.5 g; glucose, 267 g. The individual calorie contents of breakfast, lunch, snacks, and supper were 356, 324, 355 and 324 kcal, respectively (Enimaclin® diet; Glico Co., Tokyo, Japan). Meals were given at 07.00 hours (breakfast), 12.00 hours (lunch), 15.00 hours (snack), and 19.00 hours (supper). No additional food was allowed, and 100 mL of tap water was allowed only when the subjects felt thirsty. All subjects were instructed to remain upright until 22.30 hours, and then to remain in the recumbent position all night until 06.30 hours.

The percentage of time with an intragastric pH < 4.0 and the median pH values were calculated during daytime (06.30–22.30 hours), night-time (22.30–06.30 hours), the preprandial period (total time of 2 h before each meal), and postprandial period (total time of 2 h after the start of each meal).

This study was approved by the ethical committee of Shimane Medical University and written informed consent was obtained from all subjects prior to entry into the study.

Statistical analysis

Statistical analysis between different genotype groups was performed using the Mann–Whitney U-test when a significant difference was observed by the Kruskal–Wallis test. Statistical analysis between the no-medication, rabeprazole-treated, and lansoprazole-treated groups was performed using the Wilcoxon signed rank test. A P-value of < 0.05 was considered to be statistically significant.

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. SUBJECTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. References

The 20 subjects investigated were divided into three groups on the basis of their CYP2C19 genotype. Seven subjects (35%) were homo-EMs, 9 (45%) were hetero-EMs, and 4 (20%) were PMs, respectively. Age and body weight were not significantly different between each group, as shown in Table 1.

Table 1.  . Characteristics of subjects Thumbnail image of

The 24-h pH (median pH per hour) trendgram and the parameters of intragastric pH of each group (homo-EMs, hetero-EMs and PMs) obtained without medication are shown in Figure 1 and Table 2. There was no significant difference in any of the parameters in intragastric pH between the CYP2C19 genotype groups.

image

Figure 1. .  Twenty-four-hour gastric median pH trendgrams of subjects without medication in each CYP2C19 genotype (homo-EMs: ●, hetero-EMs: ▮, and PMs: ▵).

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Table 2.  . CYP2C19 genotype status and intragastric pH without medication Thumbnail image of

The 24-h pH (median pH per hour) trendgram obtained with lansoprazole and rabeprazole medication are shown in Figures 2 and 3, respectively. CYP2C19 genotype status and parameters of intragastric pH with rabeprazole and lansoprazole medication are shown in Tables 3 and 4, respectively. Gastric acid secretion was significantly suppressed during rabeprazole or lansoprazole dosing in all the CYP2C19 genotype groups (Figure 4).

image

Figure 2. .  Twenty-four-hour gastric median pH trendgrams of subjects with rabeprazole medication in each CYP2C19 genotype (homo-EMs: ●, hetero-EMs: ▮, and PMs: ▵).

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image

Figure 3. .  Twenty-four-hour gastric median pH trendgrams of subjects with lansoprazole medication in each CYP2C19 genotype (homo-EMs: ●, hetero-EMs: ▮, and PMs: ▵).

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Table 3.  . CYP2C19 genotype status and intragastric pH during rabeprazole medication Thumbnail image of
Table 4.  . CYP2C19 genotype status and intragastric pH during lansoprazole medication Thumbnail image of
image

Figure 4. .  Median pH of 24-h without, with rabeprazole, and with lansoprazole medication in individuals of each CYP2C19 genotype (homo-EMs: ●, hetero-EMs: ▮, and PMs: ▵).

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The acid suppressing effect of rabeprazole was not influenced by CYP2C19 genotype (Table 3 and Figure 4). On the other hand, the potency of the effect of lansoprazole on gastric acid secretion was significantly influenced by CYP2C19 genotype (Table 4 and Figure 4).

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. SUBJECTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. References

Proton pump inhibitors have been widely used for the treatment of acid-related diseases and in eradication therapy for H. pylori infection.3, 4, 25[26]–27 As proton pump inhibitors inhibit the function of the proton pump responsible for the terminal step in gastric acid secretion, they are considered to be the most effective treatment for gastric acid suppression.3, 4 However, interindividual variation in the metabolism of omeprazole has been reported to cause interindividual differences in the acid suppressing effect of omeprazole.18

CYP2C19, one of the CYP isoenzymes in the liver, is known to have important roles in the catabolism of several proton pump inhibitors. However, the relative contribution of CYP2C19-mediated metabolism varies among the different proton pump inhibitors.13[14][15][16]–17, 24 Individuals can be divided into EMs and PMs on the basis of their CYP2C19 phenotype, which is genetically determined.19, 20 The ratios of plasma drug concentration (area under the curve) in PMs vs. EMs after administration of omeprazole, pantoprazole, lansoprazole, and rabeprazole were reported to be 6.3, 6.0, 4.3 and 1.8, respectively.19, 28, 29 Therefore, the relative contribution of CYP2C19-mediated metabolism to the catabolism of the proton pump inhibitors should be omeprazole ≈ pantoprazole > lansoprazole > rabeprazole.24

Genotyping analysis by PCR-RFLP methods divides the population into three genotype groups for CYP2C19: homo-EMs, hetero-EMs and PMs.23 Furuta and his co-workers showed that the efficacy of gastric acid suppression by a single 20 mg dose of omeprazole was influenced by CYP2C19 genotype.18 They reported that intragastric pH during omeprazole medication in PMs was significantly higher than in homo-EMs or hetero-EMs. In this study, we tested whether the acid suppressing effect of long-term treatment with proton pump inhibitors was influenced by CYP2C19 genotype, since their repeated administration is a more appropriate model of treatment for acid-related diseases. Furthermore, we selected subjects without H. pylori infection in order to exclude any possible effect of H. pylori infection on proton pump inhibitor-induced acid suppression. As the majority of patients with reflux oesophagitis have been reported not to have H. pylori infection,30[31]–32 our experimental setting fits a situation where proton pump inhibitors are used as treatment for patients with reflux oesophagitis. Our present study demonstrated that the acid suppressing effect of long-term treatment with lansoprazole was influenced by CYP2C19 genotype, even without the influence of H. pylori infection, as was previously reported for single doses of omeprazole. On the other hand, the potency of rabeprazole for acid suppression was less dependent on CYP2C19 genotype than lansoprazole. These findings fit quite well with the data obtained by measuring plasma proton pump inhibitor concentrations in EMs and PMs. Thus, we confirmed by a direct measurement of 24-h intragastric pH that the acid suppressing effect of rabeprazole, but not that of lansoprazole, was not significantly influenced by CYP2C19 genotype.

Proton pump inhibitors have been widely used, not only for the treatment of acid-related diseases but also in eradication therapy for H. pylori infection.25[26]–27 Their role in H. pylori eradication therapy is to inhibit gastric acid secretion and to elevate intragastric pH with resulting potentiation of the antimicrobial effect of amoxycillin and clarithromycin.33[34]–35 Therefore, when proton pump inhibitors that are catabolized by CYP2C19 are administered to PMs, the eradication rate of H. pylori may be augmented. Indeed, several reports have shown that high rates of eradication were possible with omeprazole-based eradication therapy in PMs, but not in EMs.36, 37 Our present study also suggested the possibility that the potency of lansoprazole-based eradication therapy, but not that of rabeprazole-based therapy, may be enhanced in PMs. The distribution of PMs is reported to show a considerable interethnic variation. For example, Oriental people, including Chinese, Koreans and Japanese, have 13–23% PMs in their population, whereas Caucasians and African–Americans have only less than 6%.19, 20, 23, 38[39][40][41][42]–43 Since Orientals have a high H. pylori infection rate,44[45][46]–47 the high frequency of CYP2C19 PMs in this population may influence eradication rates with proton pump inhibitor-based therapy, except for those based on rabeprazole.

In conclusion, our study has demonstrated that the CYP2C19 genotype influences the potency of lansoprazole-induced, but not of rabeprazole-induced, gastric acid suppression.

Acknowledgements

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. SUBJECTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. References

We wish to thank Ms Rika Tohma, Ms Kiyoe Ueda, and Ms Keiko Masuzaki for their technical support. This work was supported in part by Grants-in-Aid for Scientific Research from the Ministry of Education, Science and Culture of Japan.

References

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. SUBJECTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. References
  • 1
    Hunt RH, Cederberg C, Dent J, et al. Optimizing acid suppression for treatment of acid-related diseases. Dig Dis Sci 1995; 40(S2): 2449.
  • 2
    Bell NJV, Hunt RH. Role of gastric acid suppression in the treatment of gastro-oesophageal reflux disease. Gut 1992; 33: 11824.
  • 3
    Sachs G. Proton pump inhibitors and acid-related diseases. Pharmacotherapy 1997; 17: 2237.
  • 4
    Williams MP, Pounder RE. Review article: the pharmacology of rabeprazole. Aliment Pharmacol Ther 1999; 13(S3): 310.
  • 5
    Klinkenberg-knol EC, Meuwissen SGM. Combined gastric and oesophageal 24-hour pH monitoring and oesophageal manometry in patients with reflux disease, resistant to treatment with omeprazole. Aliment Pharmacol Ther 1990; 4: 48595.
  • 6
    Leite LP, Johnston BT, Just RJ, Castell DO. Persistent acid secretion during omeprazole therapy: a study of gastric acid profiles in patients demonstrating failure of omeprazole therapy. Am J Gastroenterol 1996; 91: 152731.
  • 7
    Katzka DA, Paoletti V, Leite L, Castell DO. Prolonged ambulatory pH monitoring in patients with persistent gastroesophageal reflux disease symptoms: testing while on therapy identifies the need for more aggressive anti-reflux therapy. Am J Gastroenterol 1996; 91: 21103.
  • 8
    Verdú EF, Armstrong D, Fraser R, et al. Effect of Helicobacter pylori status on intragastric pH during treatment with omeprazole. Gut 1995; 36: 53943.
  • 9
    Kuipers EJ, Lee A, Klinkenberg KEC, Meuwissen SGM. Review article: the development of atrophic gastritis-Helicobacter pylori and the effects of acid suppressive therapy. Aliment Pharmacol Ther 1995; 9: 33140.
  • 10
    Labenz J, Tillenburg B, Peitz U, et al. Helicobacter pylori augments the pH-increasing effect of omeprazole in patients with duodenal ulcer. Gastroenterology 1996; 110: 72532.
  • 11
    Gillen D, Wirz AA, Neithercut WD, Ardill JES, McColl KEL. Helicobacter pylori infection potentiates the inhibition of gastric acid secretion by omeprazole. Gut 1999; 44: 46875.
  • 12
    Holtmann G, Cain C, Malfertheiner P. Gastric Helicobacter pylori infection accelerates healing of reflux esophagitis during treatment with the proton pump inhibitor pantoprazole. Gastroenterology 1999; 117: 116.
  • 13
    Andersson T. Pharmacokinetics, metabolism and interactions of acid pump inhibitors. Focus on omeprazole, lansoprazole and pantoprazole. Clin Pharmacokinet 1996; 31: 928.
  • 14
    Meyer UA. Metabolic interactions of the proton-pump inhibitors lansoprazole, omeprazole and pantoprazole with other drugs. Eur J Gastroenterol Hepatol 1996; 8(S1): 215.
  • 15
    Pearce RE, Rodrigues AD, Goldstein JA, Parkinson A. Identification of the human P450 enzymes involved in lansoprazole metabolism. J Pharmacol Exp Ther 1996; 277: 80516.
  • 16
    Yasuda S, Horai Y, Tomono Y, et al. Comparison of the kinetic disposition and metabolism of E3810, a new proton pump inhibitor, and omeprazole in relation to S-mephenytoin 4′-hydroxylation status. Clin Pharmacol Ther 1995; 58: 14354.
  • 17
    VandenBranden M, Ring BJ, Binkley SN, Wrighton SA. Interaction of human liver cytochromes P450 in vitro with LY307640, a gastric proton pump inhibitor. Pharmacogenetics 1996; 6: 8191.
  • 18
    Furuta T, Ohashi K, Kosuge K, et al. CYP2C19 genotype status and effect of omeprazole on intragastric pH in humans. Clin Pharmacol Ther 1999; 65: 55261.
  • 19
    Küpfer A, Preisig R. Pharmacogenetics of mephenytoin: a new drug hydroxylation polymorphism in man. Eur J Clin Pharmacol 1984; 26: 7539.
  • 20
    Wedlund PJ, Aslanian WS, McAllister CB, Wilkinson GR, Branch RA. Mephenytoin hydroxylation deficiency in Caucasians: frequency of a new oxidative drug metabolism polymorphism. Clin Pharmacol Ther 1984; 36: 77380.
  • 21
    De Morais SMF, Wilkinson GR, Blaisdell J, et al. The major genetic defect responsible for the polymorphism of S-mephenytoin metabolism in humans. J Biol Chem 1994; 269: 1541922.
  • 22
    De Morais SMF, Wilkinson GR, Blaisdell J, et al. Identification of a new genetic defect responsible for the polymorphism of S-mephenytoin metabolism in Japanese. Mol Pharmacol 1994; 46: 5948.
  • 23
    Kubota T, Chiba K, Ishizaki T. Genotyping of S-mephenytoin 4′-hydroxylation in an extended Japanese population. Clin Pharmacol Ther 1996; 60: 6616.
  • 24
    Ishizaki T, Horai Y. Review article: cytochrome P450 and the metabolism of proton pump inhibitors—emphasis on rabeprazole. Aliment Pharmacol Ther 1999; 13(S3): 2736.
  • 25
    Goodwin CS, Mendall MM, Northfield TC. Helicobacter pylori infection. Lancet 1997; 349: 2659.
  • 26
    Walsh JH, Peterson WL. The treatment of Helicobacter pylori infection in the management of peptic ulcer disease. N Engl J Med 1995; 333: 98491.
  • 27
    Penston JG, McColl KE. Eradication of Helicobacter pylori: an objective assessment of current therapies. Br J Clin Pharmacol 1997; 43: 22343.
  • 28
    Sohn D-R, Kwon J-T, Kim H-K, Ishizaki T. Metabolic disposition of lansoprazole in relation to the S-mephenytoin 4′-hydroxylation phenotype status. Clin Pharmacol Ther 1997; 61: 57482.
  • 29
    Tanaka M, Ohkubo T, Otani K, et al. Metabolic disposition of pantoprazole, a proton pump inhibitor, in relation to S-mephenytoin 4′-hydroxylation phenotype and genotype. Clin Pharmacol Ther 1997; 62: 61928.
  • 30
    Werdmuller BFM, Loffeld RJLF. Helicobacter pylori infection has no role in the pathogenesis of reflux esophagitis. Dig Dis Sci 1997; 42: 1035.
  • 31
    Varanasi RV, Fantry GT, Wilson KT. Decreased prevalence of Helicobacter pylori infection in gastroesophageal reflux disease. Helicobacter 1998; 3: 18894.
  • 32
    Koike T, Ohara S, Sekine H, et al. Helicobacter pylori infection inhibits reflux esophagitis by inducing atrophic gastritis. Am J Gastroenterol 1999; 94: 346872.
    Direct Link:
  • 33
    Grayson ML, Eliopoulos GM, Ferraro MJ, Moellering RC. Effect of varying pH on the susceptibility of Campylobacter pylori to antimicrobial agents. Eur J Clin Microbiol Infect Dis 1989; 8: 8889.
  • 34
    Labenz J, Stolte M, Blum AL, et al. Intragastric acidity as a predictor of the success of Helicobacter pylori eradication: a study in peptic ulcer patients with omeprazole and amoxicillin. Gut 1995; 37: 3943.
  • 35
    Goddard AF, Jessa MJ, Barrett DA, et al. Effect of omeprazole on the distribution of metronidazole, amoxicillin, and clarithromycin in human gastric juice. Gastroenterology 1996; 111: 35867.
  • 36
    Furuta T, Ohashi K, Kamata T, et al. Effect of genetic differences in omeprazole metabolism on cure rates for Helicobacter pylori infection and peptic ulcer. Ann Intern Med 1998; 129: 102730.
  • 37
    Aoyama N, Tanigawara Y, Kita T, et al. Sufficient effect of 1-week omeprazole and amoxicillin dual treatment for Helicobacter pylori eradication in cytochrome P450 2C19 poor metabolizers. J Gastroenterol 1999; 34(S XI): 803.
  • 38
    Jacqz E, Dulac H, Mathieu H. Phenotyping polymorphic drug metabolism in the French Caucasian population. Eur J Clin Pharmacol 1988; 35: 16771.
  • 39
    Sanz EJ, Villén T, Alm C, Bertilsson L. S-mephenytoin hydroxylation phenotypes in a Swedish population determined after coadministration with debrisoquin. Clin Pharmacol Ther 1989; 45: 4959.
  • 40
    Horai Y, Nakano M, Ishizaki T, et al. Metoprolol and mephenytoin oxidation polymorphisms in Far Eastern Oriental subjects: Japanese versus mainland Chinese. Clin Pharmacol Ther 1989; 46: 198207.
  • 41
    Bertilsson L, Lou Y-Q, Du Y-L, et al. Pronounced differences between native Chinese and Swedish populations in the polymorphic hydroxylations of debrisoquin and S-mephenytoin. Clin Pharmacol Ther 1992; 51: 38897.
  • 42
    Sohn D-R, Kusaka M, Ishizaki T, et al. Incidence of S-mephenytoin hydroxylation deficiency in a Korean population and the interphenotypic differences in diazepam pharmacokinetics. Clin Pharmacol Ther 1992; 52: 1609.
  • 43
    Edeki TI, Goldstein JA, De Morais SM, et al. Genetic polymorphism of S-mephenytoin 4′-hydroxylation in African-Americans. Pharmacogenetics 1996; 6: 35760.
  • 44
    Asaka M, Kimura T, Kudo M, et al. Relationship of Helicobacter pylori to serum pepsinogens in an asymptomatic Japanese population. Gastroenterology 1992; 102: 7606.
  • 45
    Youn H-S, Baik S-C, Cho Y-K, et al. Comparison of Helicobacter pylori infection between Fukuoka, Japan and Chinju. Korea Helicobacter 1998; 3: 914.
  • 46
    Ma J-L, You W-C, Gail M-H, et al. Helicobacter pylori infection and mode of transmission in a population at high risk of stomach cancer. Int J Epidemiol 1998; 27: 5703.
  • 47
    Lin J-T, Wang J-T, Wang T-H, et al. Helicobacter pylori infection in a randomly selected population, healthy volunteers, and patients with gastric ulcer and gastric adenocarcinoma. A seroprevalence study in Taiwan. Scand J Gastroenterol 1993; 28: 106772.