2013--埃索美拉唑VS奥、兰、雷一天两次对于CYP2C19代谢研究

Twice-daily dosing of esomeprazole effectively inhibits acid secretion in CYP2C19rapid metabolisers compared with twice-daily omeprazole,rabeprazole or lansoprazoleS.Sahara*,M.Sugimoto*,T.Uotani*,H.Ichikawa*,M.Yamade*,M.Iwaizumi †,T.Yamada*,S.Osawa ‡,K.Sugimoto*,K.Umemura §,H.Miyajima*&T.Furuta ¶*First Department of Medicine,Hamamatsu University School of Medicine,Hamamatsu,Japan.†Department of Clinical Oncology,Hamamatsu University School of Medicine,Hamamatsu,Japan.‡Department of Endoscopic andPhotodynamic Medicine,Hamamatsu University School of Medicine,Hamamatsu,Japan.§Department of Pharmacology,Hamamatsu University School of Medicine,Hamamatsu,Japan.¶Center for Clinical Research,Hamamatsu University School of Medicine,Hamamatsu,Japan.Correspondence to:Dr M.Sugimoto,First Department of Medicine,Hamamatsu University School of Medicine,1-20-1,Handayama,Hamamatsu 431-3192,Japan.E-mail:mitsu@hama-med.ac.jpPublication dataSubmitted 11July 2013First decision 24July 2013Resubmitted 22August 2013Accepted 28August 2013EV Pub Online 16September 2013SUMMARYBackgroundTwice-daily dosing of proton pump inhibitors (PPIs)is used to treat Helicobacter pylori or acid-related diseases,such as gastro-oesophageal re flux disease (GERD)refractory to standard dose of a PPI.Genetic polymorphisms of CYP2C19are involved to different extents in the metabolism of four kinds of PPIs (omepra-zole,lansoprazole,rabeprazole and esomeprazole)available in Japan.MethodsWe performed 24-h pH monitoring studies on Day 7of PPI treatment for 40Japanese H.pylori-negative volunteers [15CYP2C19rapid metabolisers (RMs),15intermediate metabolisers (IMs)and 10poor metabolisers (PMs)]using a randomised four-way crossover design:omeprazole 20mg,esomep-razole 20mg,lansoprazole 30mg and rabeprazole 10mg twice daily.ResultsAlthough median pH values with esomeprazole,omeprazole,lansoprazole and rabeprazole were 5.7(3.5–7.2),5.5(2.4–7.2),5.5(3.7–7.3)and 5.2(2.5–7.3),respectively (no statistically signi ficant differences),CYP2C19geno-type-dependent differences were smaller for esomeprazole and rabeprazole compared with values for omeprazole and lansoprazole.In CYP2C19RMs,the median pH with esomeprazole [5.4(3.5–6.8)]was signi ficantly higher than those with omeprazole [5.0(2.4–5.9),P =0.018],lansoprazole [4.7(3.7-5.5),P =0.017]or rabeprazole [4.8(2.5–6.4),P =0.002].In IMs and PMs,the median pH was >5.0independent of the PPI.Aliment Pharmacol Ther 2013;38:1129–1137ª2013John Wiley &Sons Ltd 1129doi:10.1111/apt.12492Alimentary Pharmacology and TherapeuticsINTRODUCTIONGiven the importance of rapidly and potently neutralis-ing intragastric pH in the treatment of acid-related dis-eases such as peptic ulcer or gastro-oesophageal reflux disease(GERD),proton pump inhibitors(PPIs)have enjoyed widespread use in treatment regimens.1–4PPIs undergo extensive hepatic metabolism by the cytochrome P450(CYP)enzyme system,particularly by CYP2C19.5More than20variants of the CYP2C19gene have been discovered,and the pharmacokinetics and pharmacodynamics(i.e.intragastric pH)of PPIs differ by CYP2C19genotypes.6–8The majority of Japanese people can be classified into three genotypes[rapid met-aboliser(RM),intermediate metaboliser(IM)and poor metaboliser(PM)]based on the CYP2C19wild-type gene and two mutated alleles(*2and*3).5,9–11While a fourth genotype,ultra rapid metaboliser(UM),which is marked by a mutated*17allele,has also been classified, its incidence in Japan is extremely low.12In PMs,plasma PPI levels are markedly increased and acid inhibition by a PPI is enhanced compared with RMs and IMs.7,8,13–15On the other hand,acid inhibition in RMs is weak compared with IMs and PMs and cure rates of acid-related diseases by PPI-based therapy in RMs are low,7,8,13–15indicating that CYP2C19genotype pro-foundly influences success of PPI treatment.An impor-tant point is that prevalence of CYP2C19genotype status differs among different races:prevalence of CYP2C19RMs is56–69%in Caucasians,81%in Afri-can-Americans,27–35%in Japanese,38%in Chinese and13%in Koreans(13%).5Four types of PPIs are currently available in Japan: omeprazole,lansoprazole,rabeprazole and esomeprazole. Of these,omeprazole and lansoprazole arefirst-genera-tion PPIs and primarily metabolised by CYP2C19and CYP3A4.5Therefore,large differences in the plasma con-centrations of omeprazole and lansoprazole are observed among CYP2C19genotypes,and these differences influ-ence the degree of inhibition of acid secretion.13In con-trast,the second-generation PPI,rabeprazole,is metabolised mainly via a non-enzymatic pathway with minor CYP2C19and CYP3A4involvement.5Therefore, the acid-inhibitory activity of rabeprazole is less influ-enced by the CYP2C19genotype than omeprazole or lansoprazole.7Esomeprazole,the S-isomer of omeprazole, also more effectively inhibits acid secretion than omepra-zole,16,17and because of its less extensivefirst-pass hepatic metabolism than omeprazole,a high plasma level of esomeprazole can be attained and sustained for a longer time than with omeprazole.17The increased sys-temic bioavailability of esomeprazole offers the prospect of improved clinical efficacy and more effective manage-ment for acid-related diseases than omeprazole.How-ever,while this pharmacokinetic advantage translates into more effective and more sustained acid inhibition compared with other PPIs in Western populations,no supporting data have been generated in Japanese popula-tions.18Twice-daily dosing of a PPI is used to eliminate Heli-cobacter pylori or treat patients with GERD refractory to standard dose of a PPI.Because clarithromycin and amoxicillin are acid-sensitive,acid secretion must be potently inhibited by a PPI to prevent the degradation of these antibiotics at low pH.19However,previous studies have indicated difficulty in sustaining high pH over 24h,especially in CYP2C19RMs,resulting in the eradi-cation rate in RMs being poorest among the three geno-types when receivingfirst-generation PPIs.14,20,21 Despite this unmet need,however,whether or not twi-ce-daily dosing of esomeprazole or rabeprazole can attain the necessary acid inhibition for H.pylori eradication in CYP2C19RMs has not been fully elucidated.Similarly, to control of severity and incidence rate of reflux erosive oesophagitis by PPI treatment have been reported to depend on CYP2C19genotype.3,22–25The control of severity and incidence rate of reflux erosive oesophagitis, intragastric pH must be sustained above4.0for20h per day;26however,as mentioned before,whether or not twi-ce-daily dosing of second-generation PPIs can attain this level of acid inhibition in CYP2C19RMs is unknown. Here,to determine whether the acid inhibition attained by twice-daily dosing with esomeprazole and rabeprazole is influenced by CYP2C19genotype and compare the acid-inhibitory effects of four PPIs dosed twice daily(marketed doses in Japan)in Japanese popu-lations,we conducted a study in healthy Japanese volun-teers.MATERIALS AND METHODSStudy protocolThe inhibition of gastric acid secretion over24h by four PPIs(omeprazole,lansoprazole,rabeprazole and esomep-razole)was observed in young Japanese subjects categor-ised as one of three CYP2C19genotypes:RM,IM or PM.All subjects gave written informed consent prior to the trial.The study was approved by the Ethics Com-mittee of Hamamatsu University School of Medicine,1130Aliment Pharmacol Ther2013;38:1129-1138ª2013John Wiley&Sons LtdS.Sahara et al.Hamamatsu,Japan,and was performed in accordance with the ethical principles of the Declaration of Helsinki. The study was performed as a randomised four-way crossover design.Subjects were dosed a PPI twice daily (at8:00AM and at7:30PM)for7days using the stan-dard dose of H.pylori eradication in Japan as follows: omeprazole20mg(Omepral;AstraZeneca,Osaka, Japan),esomeprazole20mg(Nexium;AstraZeneca),lan-soprazole30mg(Takepron;Takeda,Tokyo,Japan)and rabeprazole10mg(Pariet;Eisai,Tokyo,Japan).In addi-tion,40H.pylori-negative healthy young Japanese indi-viduals without any gastrointestinal symptoms were recruited and gave written informed consent(CYP2C19 genotype;RM,n=15,IM,n=15and PM,n=10).We excluded subjects with H.pylori infection,a history of H. pylori eradication therapy,a significant clinical illness (e.g.malignancy)or those who were taking any medica-tions[e.g.acid-suppressant drugs,nonsteroidal anti-inflammatory drugs(NSAIDs),antibiotics or cal-cium channel blockers]from the study.A24-h pH monitoring study was performed before the trial as a control and on day7of each regimen.At first,an antimony pH catheter was inserted transnasally into all subjects after they were provided a low-fat break-fast;they were then provided two low-fat meals[lunch (591kcal)at12:00PM,dinner(611kcal)at7:00PM] after the electrode monitoring was commenced.Mineral water was allowed ad libitum,but no other beverages were permitted.No subjects consumed alcohol or smoked,and none took any medications from at least 2weeks before and during the study.H.pylori status and CYP2C19genotyping Helicobacter pylori infection was determined using a serological test(E plate Eiken H.pylori antibody;Eiken Chemical Co.Ltd,Tochigi,Japan).DNA was extracted from leucocytes of a blood sample using a commercially available kit(Wizard Genomic DNA Purification Kit; Promega,Madison,WI,USA).Genotyping procedures for identifying the CYP2C19wild-type gene and two mutated alleles,CYP2C19*2and*3,were performed via the allele-specific primer-polymerase chain reaction (ASP-PCR)assay.All subjects were then classified into three groups,namely RMs,IMs and PMs. Measurement of intragastric pH24-h pH monitoring was started at8:00AM on Day7of each trial.An antimony pH catheter(Synectics Medical, Barcarena,Portugal)linked to a Digitrapper record sys-tem(Sierra Scientific Instruments,LLC,Los Angeles,CA,USA)was inserted transnasally underfluoroscopic guidance and placed approximately5cm below the lower oesophageal sphincter30min before drug admin-istration.Statistical analysisAge,height and body weight are expressed as meanÆs.d.Intragastric pH and the percentage time of pH>4over the24-h period are expressed as the median (with range).Statistically significant differences among CYP2C19genotypes in each regimen were determined using the Mann–Whitney U-test if a significant differ-ence was observed using the Kruskal–Wallis test.Statisti-cally significant differences among different regimens were determined using the Wilcoxon signed rank test. All P values are two-sided,and P values<0.05are con-sidered statistically significant.Calculations were carried out using the statistical software StatView5.0(SAS Insti-tute,Cary,NC,USA).RESULTSAll40H.pylori-negative subjects completed the study from October2011to December2012.No subjects expe-rienced any severe adverse events.There were no signifi-cant differences in backgrounds among the three CYP2C19genotype groups(Table1).The median24-h pH–time curves of each PPI increased compared with controls(nontreatment)and were similar among four kinds of PPIs over24h (Figure1a).The median(range)pH for the control was 1.5(0.7–3.1),which was significantly lower than those values for esomeprazole[5.7(3.5–7.2)],omeprazole[5.5 (2.4–7.2)],lansoprazole[5.5(3.7–7.3)]and rabeprazole [5.2(2.5–7.3)](all P<0.001)(Figure1b).Similarly, when we compared the percentage time of pH>4of control for each PPI regimen,statistically significant dif-ferences were observed(all P<0.001)(Figure1c).How-ever,no significant differences in median pH and percentage time of pH>4were noted among the four PPIs,except when comparing esomeprazole and rabep-razole(P<0.001)(Figure1b,c).Although the24-h pH–time curves for omeprazole and lansoprazole differed among the CYP2C19geno-types,differences for esomeprazole and rabeprazole between the genotypes appeared smaller(Figure2a–d). The24-h median(range)pH for esomeprazole in PMs was 6.2(5.2–7.2),which was significantly higher than those values in RMs[5.4(3.5–6.8),P=0.018]or IMs [5.6(4.3–6.8),P=0.017](Figure2e).When omeprazole or lansoprazole were dosed,significant differences inAliment Pharmacol Ther2013;38:1129-11381131ª2013John Wiley&Sons LtdEsomeprazole inhibits acid secretion in CYP2C19rapid metabolisers24-h median pH values were observed among CYP2C19genotypes [omeprazole:RMs, 5.0(2.4–5.9),IMs, 5.7(4.5–6.5)and PMs,6.6(5.5–7.2);and lansoprazole:RMs,4.7(3.7–5.5),IMs,5.4(4.7–6.9)and PMs,6.4(5.5–7.3);P <0.05](Figure 2e).Signi ficant differences were noted between RMs and PMs and between IMs and PMs in percentage time of pH >4for esomeprazole and omepra-zole (P <0.05respectively)(Figure 2f).For rabeprazole,the median pH and percentage time of pH >4signi fi-cantly differed only between RMs and PMs (Figure 2e,f).These observations suggest that acid inhibition by thetwice-daily dosing of any of the PPIs,including esomep-razole,differed among the CYP2C19genotypes in H.pylori -negative Japanese subjects.In CYP2C19RMs,the median (range)pH of esomep-razole [5.4(3.5–6.8)]was signi ficantly higher than that of omeprazole [5.0(2.4–5.9),P =0.018],lansoprazole [4.7(3.7–5.5),P =0.017]or rabeprazole [4.8(2.5–6.4),P =0.002](Figure 3a).Esomeprazole alone attained an intragastric pH higher than 5.0in RMs.In PMs,the median (range)percentage time of pH >4with omepra-zole [94.5%(84.8–100%)]was signi ficantly higherthanAge (years)21.7Æ1.722.1Æ1.521.7Æ2.021.2Æ1.80.473Height (cm)169.7Æ8.4168.7Æ10.9167.6Æ7.0167.2Æ6.80.853Weight (kg)59.7Æ9.960.4Æ12.259.5Æ8.158.7Æ9.30.969CYP2C19genotypes*1/*1:n =15*1/*2:n =11*1/*3:n =4*2/*2:n =5*2/*3:n =48161220424Time875630412875630412RPZOPZ LPZ EPZ Control Control EPZ LPZ OPZ RPZ Control EPZ LPZ OPZ RPZ1008060402001132Aliment Pharmacol Ther 2013;38:1129-1138ª2013John Wiley &Sons LtdS.Sahara et al.that with esomeprazole [87.2%(71.6–99.2%),P =0.017]or rabeprazole [86.6%(21.0–99.2%),P =0.047](Figure 3b).However,the median of intragastric pH was higher than 5.0in all IMs and PMs independent of the PPI.DISCUSSIONWe demonstrated that the 24-h pH values attained over-all with twice-daily dosing of PPIs were equivalent among the four kinds of PPIs available in Japan.How-ever,the variations in acid inhibition associated with the CYP2C19genotype were small for esomeprazole and rabeprazole compared with values for omeprazole and lansoprazole.In H.pylori -negative Japanese subjects with CYP2C19RMs,median pH was signi ficantly higher with esomeprazole than with the other three PPIs.Although median pH in PMs was signi ficantly higher with omep-razole than with other PPIs,including esomeprazole,acid inhibition attained by any of the four PPIs in IMs and PMs was suf ficient for treatment of GERD and H.pylorieradication.4,26–28Therefore,although in fluence of CYP2C19genotype status on acid inhibition cannot be ignored,we deem esomeprazole to be preferable PPI for use in treating acid-related diseases,particularly in Japa-nese with CYP2C19RMs.In RMs,PPIs were rapidly eliminated from the sys-temic circulation,and plasma PPI levels before and 3h after dosing were often below detectable levels,resulting in insuf ficient acid inhibition.Following the rapid elimi-nation of PPIs,newly generated or activated H +,K +-ATPases in gastric parietal cells are able to secrete gastric acid.6–8,13However,acid inhibition by PPIs has also been observed to occasionally be insuf ficient,even if dosed twice daily in CYP2C19RMs.8Because the phar-macokinetics and pharmacodynamics of PPIs differ by the dependence on CYP2C19in each metabolic path-way,7,8,13–15,29PPI with less in fluence of CYP2C19is more preferable.One attractive characteristic of esomep-razole is that it is metabolised by CYP2C19to a lesser extent than omeprazole and therefore achievespotentEsomeprazoleRabeprazoleLansoprazoleOmeprazoleR P I R P I R P I R P I 812 1620 24 4812 1620 24 4812 1620 24 4 812 1620 24 4 *******##R P I R P I R P I R P I 875630412875630412875630412875630412875630412100806040200Aliment Pharmacol Ther 2013;38:1129-11381133ª2013John Wiley &Sons LtdEsomeprazole inhibits acid secretion in CYP2C19rapid metabolisersacid inhibition over 24h,irrespective of CYP2C19geno-type.16,17,30However,because CYP3A4is also involved in the metabolism of esomeprazole,esomeprazole has the potential risk of drug –drug interaction with a variety of drugs metabolised by CYP3A4.31Physicians must pay attention to this problem.In a randomised crossover study using healthy H.pylori -negative subjects,the percentage time of pH >4with esomeprazole 20mg was signi ficantly longer than that with lansoprazole 15mg (50.4%vs.43.0%,P =0.03)or rabeprazole 10mg (59.8%vs.51.7%,P =0.01).32In the present study,the median 24-h pH with esomeprazole 20mg twice daily in H.pylori -nega-tive CYP2C19RMs was signi ficantly higher than that with omeprazole,rabeprazole or lansoprazole throughout the 24-h observation period.We therefore recommend the use of esomeprazole in patients with acid-related dis-eases,particularly those refractory to standard doses of a PPI (e.g.CYP2C19RMs).Several studies have examined the ef ficacy of twice-daily dosing of a PPI with relation to CYP2C19,with con flicting findings being reported.For example,while two studies noted CYP2C19-dependent differences inacid inhibition between lansoprazole 30mg and rabep-razole 20mg,no such differences were seen between rabeprazole 10mg and esomeprazole 20mg.33,34In the present study,the intragastric pH attained by twice-daily dosing of PPIs differed among CYP2C19genotypes.However,the CYP2C19genotype-dependent variance in intragastric pH attained by esomeprazole and rabepraz-ole was smaller than that attained by lansoprazole or omeprazole.Therefore,twice-daily dosing of second-gen-eration PPIs might overcome the in fluence of CYP2C19genotypes to some degree,although not completely.As an alternative,trials of four-times daily dosing of PPIs have also been reported,involving rabeprazole 10mg,lansoprazole 30mg and esomeprazole 10mg,all of which attained suf ficient acid inhibition in CYP2C19RMs.8,34,35Taken together,these present and previous findings therefore suggest that multiple dosing of a PPI decreases CYP2C19genotype-dependent differences in acid inhibition.Potent acid inhibition is important for the eradication of H.pylori.4Potent acid inhibition also increases the sta-bility and bioavailability of antibiotics in the stomach and the concentration of antibiotics in gastric mucosa.36–38**EPZ OPZ RPZLPZ EPZ OPZ RPZLPZ EPZ OPZ RPZLPZ EPZ OPZ RPZLPZ EPZ OPZ RPZLPZ EPZ OPZ RPZLPZ 8756304121008060402001134Aliment Pharmacol Ther 2013;38:1129-1138ª2013John Wiley &Sons LtdFurthermore,acid inhibition allows H.pylori to reach its growth phase,rendering the bacteria more sensitive to antibiotics.38We28previously reported that,in analysis of24-h pH monitoring using H.pylori-negative subjects, 24-h pH level was required to be higher than5.0,which was achieved in CYP2C19IMs with eradication rate of higher than95%.In addition,we demonstrated that the pH level over24h was significantly higher in patients who achieved successful eradication using lansoprazole-based triple therapy[6.4(5.0–7.6)]than those who did not[5.2(2.2–6.2)].4In this study,median pH with esomeprazole in H.pylori-negative CYP2C19RMs was[5.4(3.5–6.8)],but those attained with other PPIs were not higher than5.0, suggesting that esomeprazole-based eradication might be acceptable compared with other PPIs for CYP2C19RMs. We therefore will plan to show in our hypothesis that H.pylori eradication rate with esomeprazole-based regi-men is independent of the CYP2C19genotype and is higher than that with an omeprazole-,rabeprazole-or lansoprazole-based regimen in CYP2C19RM patients. PPIs improve acid reflux heartburn symptoms and oesophageal mucosal breaks.39–43Meta-analyses of treat-ments for erosive GERD patients have shown that PPIs are much more effective in curing oesophageal erosions and acid reflux-related symptoms than H2receptor antagonists.44,45Furthermore,twice-daily dosing of rab-eprazole was effective in treating patients with GERD refractory to standard doses of PPI therapy.46However, improvements in heartburn associated with non-erosive reflux disease(NERD)using standard PPI dosages are lower(ranging from30to60%)than those for erosive GERD(ranging from10to30%).47–49The development of such oesophageal mucosal damage is closely related to intraoesophageal and intragastric pH values.For effective treatment of GERD using acid-inhibitory drugs, intragastric pH over a24-h period should fall below<4.0 for no longer than2–4h.26In this study,in RMs,the median percentage time of pH<4ranged from26.6to 38.7%independent of the PPI used,suggesting that PPI twice‐daily dosing may be insufficient for treating GERD/NERD patients refractory to standard doses of a PPI.Several limitations to the present study warrant men-tion.First,the subjects were all young,healthy, H.pylori-negative volunteers,not patients.Because acid secretion and response to PPIs depend on age,the grade of gastric mucosal atrophy and H.pylori infection,our results should be extrapolated with caution to patients treated with a PPI for H.pylori eradication or GERD. Second,we did not measure the plasma PPI levels;there-fore,we could not directly correlate the metabolic dispo-sition of each PPI with the pH attainted with each PPI. Third,the sample size was small,particularly when strat-ifying data based on CYP2C19genotype group.Enrol-ment of a large population of H.pylori-positive patients will be required to show significant evidence that the cure rate of patients treated with esomeprazole-based H.pylori eradication or patients refractory to standard PPI treatment is better than that of therapy based on another stly,we investigated acid-inhibitory effects at twice-daily dosing of rabeprazole10mg(a marketed dose in Japan),not20mg(a standard dose worldwide).Therefore,the present study results cannot be extrapolated to Western patients.In general,because a dose-dependent increase in median pH and in percen-tage time of pH>4was observed for rabeprazole administered once daily in doses of5,10,20and 40mg,50further study to compare the efficacy for acid inhibition attained with twice-daily dosing of rabeprazole 20mg and esomeprazole20mg will be required.In conclusion,we demonstrated that,for Japanese people,esomeprazole is more effective than other PPIs tested for achieving potent acid inhibition when dosed twice daily in CYP2C19RMs who are at risk of being unresponsive to PPI therapy at the standard dose.The clinical potential of twice-daily dosing of esomeprazole must be verified in future studies under appropriate pro-tocols.AUTHORSHIPGuarantor of the article:None.Author contributions:All authors approved thefinal ver-sion of the manuscript.ACKNOWLEDGEMENTSDeclaration of personal interests:None.Declaration of funding interests:Grants-in-aid from the Ministry of Education,Culture,Sports,Science and Technology of Japan(23590912and23590913)and from Japan Research Foundation for Clinical Pharmacology. First Department of Medicine and The Center for Clini-cal Research at Hamamatsu University School of Medi-cine have received grants from Takeda Pharmaceutical Co.,Ltd.,AstraZeneca KK,Eisai Co.,Ltd.,Daiichi-Sankyo Co.Ltd.Aliment Pharmacol Ther2013;38:1129-11381135ª2013John Wiley&Sons LtdEsomeprazole inhibits acid secretion in CYP2C19rapid metabolisersREFERENCES1.Walsh JH,Peterson WL.The treatmentof Helicobacter pylori infection in themanagement of peptic ulcer disease.NEngl J Med1995;333:984–91.2.Furuta T,Sagehashi Y,Shirai N,et al.Influence of CYP2C19polymorphismand Helicobacter pylori genotypedetermined from gastric tissue sampleson response to triple therapy for Hpylori infection.Clin GastroenterolHepatol2005;3:564–73.3.Furuta T,Shirai N,Watanabe F,et al.Effect of cytochrome P4502C19genotypic differences on cure rates forgastroesophageal reflux disease bylansoprazole.Clin Pharmacol Ther2002;72:453–60.4.Sugimoto M,Furuta T,Shirai N,et al.Evidence that the degree and duration of acid 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