헬리코박터제균요법에있어서 CYP2C19 유전형이판토프라졸과라베프라졸포함치료법에미치는영향. Introduction 울산대학교의과대학서울아산병원소화기내과

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1 The Korean Journal of Helicobacter and Upper Gastrointestinal Research Vol. 8, No. 1, 15-19, July 2008 Influence of CYP2C19 Polymorphism on Eradication of Helicobacter pylori: Comparison between Pantoprazole Based First-line and Rabeprazole Based Second-line Therapy 헬리코박터제균요법에있어서 CYP2C19 유전형이판토프라졸과라베프라졸포함치료법에미치는영향 정준원ㆍ정훈용ㆍ최기돈ㆍ최귀숙ㆍ김도훈ㆍ정기욱ㆍ송호준ㆍ이진혁ㆍ김진호 Department of Internal Medicine, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea 울산대학교의과대학서울아산병원소화기내과 배경 / 목적 : 대부분의 Proton pump inhibitor 는 CYP2C19 에의하여대사된다. 그러므로 CYP2C19 의유전자형에따라 PPI 를포함한제균율에차이가있다고알려져있다. 본연구는 CYP2C19 유전자형이한국인환자에서 1 차와 2 차제균치료에미치는영향을평가하기위하여시행하였다. 방법 : H. pylori 에감염된 50 명의환자를대상으로하였다. 일차제균치료로 pantoprazole 40 mg, amoxicillin 1,000 mg, and clarithromycin 500 mg 을 1 일 2 회일주일간투여하였다. CYP2C19 유전자형은 melting point genotyping 방법을이용하였다. 또한 2 차제균치료에서 CYP2C19 의영향을평가하였다. 2 차제균치료는 amoxicillin 1,000 mg, metronidazole 500 mg, bismuth 600 mg, rabeprazole 20 mg 을 1 일 2 회, tetracycline 500 mg 1 일 4 회를 1 주일간사용하였다. 결과 : 환자들의평균나이는 52±13 세였고 60.0% (30/50) 가남자였다. 1 차제균치료의전반적인제균율은 74.0% (37/50) 였다. Poor metabolizer, heterozygous extensive metabolizer, homozygous extensive metabolizer 의제균율은각각 66.7% (4/6), 77.3% (17/22), 72.7% (16/22) 이었다 (p=0.94). 2 차제균치료의전체제균율은 75.0% 이었고 poor metabolizer, heterozygous extensive metabolizer, homozygous extensive metabolizer 의제균율은각각 100% (2/2), 66.7% (8/12), 80.0% (8/10) 이었다 (p=1.00). 결론 : Pantoprazole 을포함한 1 차 3 제요법과 rabeprazole 포함 2 차 4 제요법에서 H. pylori 제균율은 CYP2C19 유전형에영향을받지않았다. Clarithromycin 내성같은다른인자가제균율을결정하는데중요할것으로생각되며, 향후많은수의환자를대상으로한연구가필요하다. (The Korean Journal of Helicobacter and Upper Gastrointestinal Research 2008;8:15-19) 색인단어 : CYP2C19, Proton pump inhibitor, Helicobacter pylori, Pantoprazole, Rabeprazole Jun-Won Chung, M.D., Hwoon-Yong Jung, M.D., Kee Don Choi, M.D., Kwi-Sook Choi, M.D., Do Hoon Kim, M.D., Kee Wook Jung, M.D., Ho June Song, M.D., Gin Hyug Lee, M.D. and Jin Ho Kim, M.D. Corresponding author: Hwoon-Yong Jung, M.D. Department of Internal Medicine, University of Ulsan College of Medicine, Asan Medical Center, 388-1, Pungnap 2-dong, Songpagu, Seoul , Korea Tel: Fax: hyjung@amc.seoul.kr Introduction Eradication of H. pylori is a main treatment of peptic ulcer disease. 1 One week to 14 days of proton pump inhibitor (PPI)-based triple therapy with clarithromycin, amoxicillin or metronidazole is standard recommendation. 2,3 PPI can directly 15

2 16 The Korean Journal of Helicobacter and Upper Gastrointestinal Research: 제 8 권제 1 호 2008 suppress H. pylori and the achievement of high intragastic ph for acid-labile antibiotics. 4,5 In the other hand, the currently available PPIs are mostly metabolized by CYP2C19 (S-mephenytoin 4 -hydroxylase) in the liver. 6 Three distinct types of metabolizers have been recognized: the wild type, so-called homozygous extensive metabolizer (Homo-EM), the heterozygous extensive metabolizer (Het-EM), and finally, the poor metabolizers (PM). 7,8 Thus, rapid PPI clearance in Homo-EM is presumed to have a poorer H. pylori eradication rate than PM. According to recent meta-analysis, there were significant differences in the success rate of anti-helicobacter therapy between the Homo-EM and PM genotypes and between the Homo-EM and Het-EM genotypes including omeprazole, lansoprazole, or rabeprazole based first line triple therapy. 9 However, there were limited data that pantoprazole based first-line or rabeprazole based second-line therapy could be affected by the CYP2C19. The purpose of this study is to evaluate whether CYP2C19 genotype could affect the pantoprazole based triple therapy or rabeprazole based second-line quadruple therapy. Patients and Methods 1. Patients This retrospective study was performed between January 2004 and March This study was approved by the institutional review board of the Asan Medical Center. The study subjects consisted of 50 patients who were treated pantoprazole based triple therapy (amoxicillin 1,000 mg b.i.d., clarithromycin 500 mg b.i.d., pantoprazole 40 mg b.i.d.) due to gastric ulcer, duodenal ulcers, or gastritis. These patients were all H. pylori positive on the basis of rapid urease test (RUT) or histology results. During same period, 24 patients treated with rabeprazole based quadraple therapy (amoxicillin 1,000 mg b.i.d., metronidazole 500 mg b.i.d., tetracycline 500 mg q.i.d., tripotassium dictrate bismuthate 600 mg b.i.d., and rabeprazole 20 mg) were also enrolled. Amoxicillin was added to the standard quadruple therapy to increase the eradication rate. 2. Method 1) CYP2C19 genotyping For CYP2C19 genotype analysis, patients peripheral blood leukocytes were obtained. CYP2C19 was determined by LightCycler R CYP2C19 Mutation detection kit. The CYP2C19 genotype were classified as wild type (*1) and mutant type (*2) using melting point genotyping. CYP2C19 genotypes were classified into the three groups, the Homo-EM (*1/*1), Het-EM (*1/*2 or *1/*3), and PM (*2/*2, *3/*3 or *2/*3). 2) Determination of H. pylori eradication H. pylori eradication was defined as a negative 13 C-urea breath 4 6 weeks after eradication treatment completion. Patients were fasted for 4 h before testing. No test meal was given, and a pre-dose breath sample was obtained. 100 mg of 13 C-urea powder (Otsuka Pharmaceutical Co., Ltd., Tokyo, Japan) dissolved in 50 ml of water was then administered orally, and a second breath sample was collected 20 minutes later. The cut-off value used was 2.5. Collected samples were analyzed using an infrared spectrophotometer UBiT-IR300 (Otsuka Electronics Co., Ltd., Osaka, Japan). In case of follow up endoscopy, RUT or histology test were also used for the determination of H. pylori eradication. 3. Statistical Analysis H. pylori eradication efficacy was analyzed using the chi-squared test or Fisher s exact test. The p value was analyzed by chi-squared test applying the linear-by-linear association model to determine whether the H. pylori eradication rate was significantly reduced in the patients order ranked in a trendem. Analyses were performed using the Statistical Package for the Social Sciences (version 12.0; SPSS Inc. Chicago, IL, USA). p values of <.05 were considered statistically significant. Results 1. Demographic feature of patients A total of 50 H. pylori positive patients were enrolled for the primary treatment group. The mean age was 52±13, 60% (n=30) were male (Table 1). The reason of eradication was peptic ulcer disease, erosive gastritis, and family history of stomach cancer. 2. Eradication rate of primary pantoprazole based triple therapy according to CYP2C19 genetic polymorphism The overall eradication rate was 74% (37/50). The

3 Jun-Won Chung, et al:influence of CYP2C19 Polymorphism on Helicobacter Eradication Therapy 17 Table 1. Demographic characteristics of pantoprazole based therapy Table 2. Eradication rate of pantoprazole based triple therapy according to CYP2C19 genetic polymorphism CYP2C19 genotype Eradication rate Homozygous entensive metabolizer 72.7% (16/22)* Heterozygous entensive metabolizer 77.3% (17/22)* Poor metabolizer 66.6% (4/6)* Overall eradication rate 74.0% (37/50) *p=0.94. Total (n=50) Mean age (yr) 51.6±12.5 Gender (M/F) 30/20 Reasons of eradication Gastric ulcer 7 (14%) Duodenal ulcer 14 (28%) Gastric ulcer & duodenal ulcer 3 (6%) After EMR 7 (14%) Other causes 19 (38%) EMR, endoscopic mucosal resection. eradication rate of PM, Het-EM, Homo-EM was 66.6% (4/6), 77.3% (17/22), and 72.7% (16/22), respectively (Table 2). However, the eradication rate was not significantly different between the CYP219 genotypes (p=0.94). 3. Eradication rate of second-line rabeprazole based quadraple therapy according to CYP2C19 A total of 24 patients with persisting H. pylori infection after first-line PPI-amoxicillin-clarithromycin therapy was enrolled at the same period. The overall eradication rate was 75% (18/24). The eradication rates of PM, Het-EM, Homo-EM were 100.0% (2/2), 66.7% (8/12), and 80.0% (8/10), respectively (Table 3). The eradication rate was not significantly different according to the CYP219 genotypes (p=1.00). Discussion This study showed that CYP2C19 genotype status was not significantly associated with eradication of H. pylori by first-line triple pantoprazole, clarithromycin, and amoxicillin therapy. However, there were several conflicting reports Table 3. Eradication rate of second-line rabeprazole based quadruple therapy according to CYP2C19 genetic polymorphism CYP2C19 genotype Eradication rate Homozygous entensive metabolizer 80.0% (8/10)* Heterozygous entensive metabolizer 66.7% (8/12)* Poor metabolizer 100.0% (2/2)* Overall eradication rate 75.0% (18/24) *p=1.00. according to ethnic groups and proton pump inhibitors. Our results were in agreement with those of previous studies in Korea. 10 This could be partially explained by the PPI s property itself. Pantroprazole has lower affinities for CYP2C19 and CYP3A4, and is metabolized by a non-saturable enzyme outside the CYP system. 11,12 Another study using the rapeprazole disclosed similar result, which showed that the difference in the therapeutic efficacy of PPI among the different CYP2C19 was insignificant. 13 Our results were also consistent with two prospective randomized controlled studies in Japan and Taiwan. One study comparing omeprazole (40 mg/day) and rabeprazole (40 mg/day) based triple therapy revealed that H. pylori eradication is independent of CYP2C19 in both groups. 14 In Taiwan study, the eradication rate was not affected by CYP2C19 in the esomeprazole group but omeprazole group. 15 However, another study comparing lansoprazole (60 mg/day) and omeprazole (40 mg/day) suggested that CYP2C19 is significantly associated with success or failure of H. pylori eradication rate. 16 The reason of those conflicting results may be due to clarithromycin resistance in their regional area and inter-ethnic CYP2C19 variation. The distribution of CYP2C19 PM exhibits considerable inter-ethnic variation. Approximately 1 6% of Caucasians and African-Americans are characterized as PM by phenotyping and genotyping. In Asian population, the percentage of PM is much higher 13 23%. In Korea, the frequencies of CYP2C19 PM is estimated as 14% in Korea, and 21.3% in Japan. 17 On the other hand, the clarithromycin resistance rate was 12% in Japan and 5% in Taiwan in the above study population. If clarithromycin resistance rate of study population is high, its effect will be greater than that of CYP2C19. In Korea, clarithromycin resistance rate of H. pylori is also increasing. It was estimated that less than 10% in the 1990 and increased

4 18 The Korean Journal of Helicobacter and Upper Gastrointestinal Research: 제 8 권제 1 호 2008 to over 10% in the ,19 Another important finding of our study is that CYP2C19 genotype also could not influence the eradication rate of rabeprazole based quadruple therapy. Result from recent Korean studies showed overall one week eradication rates of a second-line therapy were % by intention to treat analysis, which was similar in our result. 20,21 There are few data about the bismuth based quadruple therapy and CYP2C19. One study reported that dual high dose therapy with lansoprazole and amoxicillin achieved a higher cure rate for H. pylori infection in patients with PM than in those with Het-EM and Homo-EM. 16 This study has important limitations. First, antibiotic resistance of H. pylori to clarithromycin was not investigated. As we mentioned above, H. pylori resistance to clarithromycin is a major factors that influence the eradication rate. Thus, the influence of antibiotic resistance on a cure rate is unclear. Second, we could not assess the factor such as drug adherence due to the retrospective study design. Hence the comparison of intention to treat or per protocol eradication rate was impossible. Future investigations including large scale and prospective design are required to determine whether pantoprazole based first-line therapy and rabeprazole based second-line quadruple therapy will be affected by CYP2C19 genotype. ABSTRACT Background/Aims: Genetic polymorphism of CYP2C19 could influence the eradication rate with PPI-based regimen. This study was conducted to evaluate the relationship between CYP2C19 polymorphism and the eradication rate of first- or second-line regimen in Korean patients. Methods: Fifty patients completed triple therapy with 40 mg of pantoprazole, 1,000 mg amoxicillin, and 500 mg of clarithromycin twice daily for one week. The genotype of CYP2C19 was determined by melting point genotyping methods. Twenty four patients who failed first line therapy were also included. The second-line regimen was as follows: amoxicillin 1,000 mg bid, metronidazole 500 mg bid, tetracycline 500 mg qid, bismuth 600 mg bid, and rabeprazole 20 mg bid for 1 week. Results: Overall eradication rate of first-line triple therapy was 74.0% (37/50). Eradication rates for first-line therapy in poor metabolizer, heterozygous extensive metabolizer (EM) and homozygous EM were 66.7% (4/6), 77.3% (17/22) and 72.7% (16/22), respectively (p=0.86). The overall cure rate of second-line regimen was 75.0% (18/24). Eradication rates were 100% (2/2), 66.6% (8/12), and 80.0% (8/10) in poor metabolizer, heterozygous EM and homozygous EM, respectively (p=1.00). Conclusions: Eradication rates of Helicobacter pylori were not different between the CYP2C19 genotypes from this limited data. However, prospective study should be performed to prove this result. Key Words: CYP2C19, Proton pump inhibitor, Helicobacter pylori, Pantoprazole, Rabeprazole References 1. Blaser MJ. Hypotheses on the pathogenesis and natural history of Helicobacter pylori-induced inflammation. Gastroenterology 1992;102: Malfertheiner P, Megraud F, O'Morain C, et al. Current concepts in the management of Helicobacter pylori infection: the Maastricht III Consensus Report. Gut 2007;56: Chey WD, Wong BC. American College of Gastroenterology guideline on the management of Helicobacter pylori infection. Am J Gastroenterol 2007;102: 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: Midolo PD, Turnidge JD, Lambert JR, Bell JM. Oxygen concentration influences proton pump inhibitor activity against Helicobacter pylori in vitro. Antimicrob Agents Chemother 1996;40: Tucker GT. The interaction of proton pump inhibitors with cytochromes P450. Aliment Pharmacol Ther 1994;8(suppl 1): Chong E, Ensom MH. Pharmacogenetics of the proton pump inhibitors: a systematic review. Pharmacotherapy 2003;23: Dickson EJ, Stuart RC. Genetics of response to proton pump inhibitor therapy: clinical implications. Am J Pharmacogenomics 2003;3: Padol S, Yuan Y, Thabane M, Padol IT, Hunt RH. The effect of CYP2C19 polymorphisms on H. pylori eradication rate in dual and triple first-line PPI therapies: a meta-analysis. Am J Gastroenterol 2006;101: Shin YS, Choi MG, Oh JH, et al. Effect of CYP2C19 genotype on the eradication rate of Helicobacter pylori infection by pantoprazole based triple therapy in Korea. Korean J Helicobacter Upper Gastrointest Res 2006;6: Huber R, Kohl B, Sachs G, Senn-Bilfinger J, Simon WA, Sturm E. The continuing development of proton pump inhibitors with particular reference to pantoprazole. Aliment Pharmacol Ther 1995;9: Stedman CA, Barclay ML. Comparison of the pharmacokinetics, acid suppression and efficacy of proton pump inhibitors. Aliment

5 Jun-Won Chung, et al:influence of CYP2C19 Polymorphism on Helicobacter Eradication Therapy 19 Pharmacol Ther 2000;14: Lee SB, Park SJ, Ryu JK, et al. Efficacy of triple therapy with rabeprazole for Helicobacter pylori infection in relation to CYP2C19 genotype. Korean J Gastroenterol 2003;42: Dojo M, Azuma T, Saito T, Ohtani M, Muramatsu A, Kuriyama M. Effects of CYP2C19 gene polymorphism on cure rates for Helicobacter pylori infection by triple therapy with proton pump inhibitor (omeprazole or rabeprazole), amoxycillin and clarithromycin in Japan. Dig Liver Dis 2001;33: Sheu BS, Kao AW, Cheng HC, et al. Esomeprazole 40 mg twice daily in triple therapy and the efficacy of Helicobacter pylori eradication related to CYP2C19 metabolism. Aliment Pharmacol Ther 2005;21: Furuta T, Shirai N, Takashima M, et al. Effect of genotypic differences in CYP2C19 on cure rates for Helicobacter pylori infection by triple therapy with a proton pump inhibitor, amoxicillin, and clarithromycin. Clin Pharmacol Ther 2001; 69: Wedlund PJ. The CYP2C19 enzyme polymorphism. Pharmacology 2000;61: Kim JJ, Reddy R, Lee M, et al. Analysis of metronidazole, clarithromycin and tetracycline resistance of Helicobacter pylori isolates from Korea. J Antimicrob Chemother 2001;47: Kim JM, Kim JS, Jung HC, Kim N, Kim YJ, Song IS. Distribution of antibiotic MICs for Helicobacter pylori strains over a 16-year period in patients from Seoul, South Korea. Antimicrob Agents Chemother 2004;48: Cheon JH, Kim N, Lee DH, et al. Efficacy of moxifloxacin-based triple therapy as second-line treatment for Helicobacter pylori infection. Helicobacter 2006;11: Choung RS, Lee SW, Jung SW, et al. Comparison of the effectiveness of quadruple salvage regimen for Helicobacter pylori infection according to the duration of treatment. Korean J Gastroenterol 2006;47: