Proton pump inhibitors an update of their clinical use and pharmacokinetics

REVIEW ARTICLEProton pump inhibitors:an update of their clinical use and pharmacokineticsShaojun Shi&Ulrich KlotzReceived:21January2008/Accepted:1July2008/Published online:5August2008#Springer-Verlag2008AbstractBackground Proton pump inhibitors(PPIs)represent drugs of first choice for treating peptic ulcer,Helicobacter pylori infection,gastrooesophageal reflux disease,nonsteroidal anti-inflammatory drug(NSAID)-induced gastrointestinal lesions(complications),and Zollinger-Ellison syndrome. Results The available agents(omeprazole/esomeprazole,lan-soprazole,pantoprazole,and rabeprazole)differ somewhat in their pharmacokinetic properties(e.g.,time-/dose-dependent bioavailability,metabolic pattern,interaction potential,genet-ic variability).For all PPIs,there is a clear relationship between drug exposure(area under the plasma concentration/ time curve)and the pharmacodynamic response(inhibition of acid secretion).Furthermore,clinical outcome(e.g.,healing and eradication rates)depends on maintaining intragastric pH values above certain threshold levels.Thus,any changes in drug disposition will subsequently be translated directly into clinical efficiency so that extensive metabolizers of CYP2C19 will demonstrate a higher rate of therapeutic nonresponse. Conclusions This update of pharmacokinetic,pharmacody-namic,and clinical data will provide the necessary guide by which to select between the various PPIs that differ—based on pharmacodynamic assessments—in their relative poten-cies(e.g.,higher doses are needed for pantoprazole and lansoprazole compared with rabeprazole).Despite their well-documented clinical efficacy and safety,there is still a certain number of patients who are refractory to treatment with PPIs(nonresponder),which will leave sufficient space for future drug development and clinical research. Keywords Proton pump inhibitors.Pharmacokinetics. Pharmacodynamics.Peptic ulcer.Reflux disease. Helicobacter pylori infectionIntroductionProton pump inhibitors(PPIs)are the mainstays in treating acid-related diseases.Since the introduction of omeprazole in1989,other PPIs became available,e.g.,lansoprazole (1995),pantoprazole(1997),rabeprazole(1999),and the S-enantiomer of omeprazole(2001).PPIs inhibit selectively and irreversibly the gastric H+/K+ATPase(the proton pump)that accomplishes the final step in acid secretion.All PPIs inhibit both basal and stimulated secretion of gastric acid,independent of the nature of parietal cell stimulation[1].PPIs undergo extensive hepatic metabolism by the cytochrome P450 (CYP)system,and CYP2C19polymorphisms have been shown to substantially influence the pharmacoki-netics,pharmacodynamics,and clinical outcome of PPIs [2,3].In addition,pharmacokinetic and pharmacody-namic differences between PPIs are reflected in their influence on both speed and degree of gastric acid suppression,which subsequently may affect their clinical efficacy[4].Eur J Clin Pharmacol(2008)64:935–951DOI10.1007/s00228-008-0538-yS.Shi:U.Klotz(*)Dr.Margarete Fischer-Bosch-Institut fürKlinische Pharmakologie,Auerbachstraße112,70376Stuttgart,Germanye-mail:ulrich.klotz@ikp-stuttgart.deS.Shi:U.KlotzUniversity of Tuebingen,Tuebingen,GermanyPresent address:S.ShiDepartment of Pharmacy of Union Hospital,Tongji Medical College,Huazhong University of Science and Technology, Wuhan,People’s Republic of ChinaPPIs are drugs of first choice for peptic ulcers(PU)and their complications(e.g.,bleeding),gastrooesophageal reflux disease(GERD),nonsteroidal anti-inflammatory drug(NSAID)-induced gastrointestinal(GI)lesions,Zol-linger-Ellison syndrome,dyspepsia,and eradication of Helicobacter pylori(H.pylori)with two antibiotics[5,6]. PPIs have demonstrated an excellent safety profile after approximately two decades of clinical use[7].There are some unspecific adverse events(AEs)such as headache, nausea,and diarrhea,but the main concern is emerging from the long-term suppression of acid secretion[8].During the last few years,much new data have been published on the pharmacological characteristics and therapeutic efficacy of PPIs.Therefore,it appears appro-priate to provide an update on the pharmacokinetics, pharmacodynamic action,and clinical use of PPIs. Pharmacokinetic propertiesPPIs are substituted benzimidazole derivatives and mem-brane-permeable,weak bases that accumulate in acid spaces of the active parietal cell as prodrugs.Here,they undergo acid-catalyzed conversion to the active sulfenic acid and sulfonamide derivatives.These bind covalently via disul-fide bridges to cysteine residues on the alpha subunit of the H+/K+ATPase,thus inhibiting acid secretion up to36h[1]. Whereas racemic PPI prodrugs possess a chiral center,the identical biological active principle(which is optically inactive)is formed from both enantiomers.The main pharmacokinetic parameters of all PPIs are compared in Table1[6,9].Omeprazole and esomeprazoleOmeprazole is administered as a racemic mixture of its two enantiomers,S-omeprazole(esomeprazole)and R-omepra-zole.Both prodrugs are acid labile and usually administered as encapsulated enteric-coated granules.After oral admin-istration,they are rapidly absorbed[9].They should be swallowed at least1h before eating.The bioavailability(F) of esomeprazole was significantly reduced when taken within15min before eating a high-fat meal compared with fasting conditions[10].When increasing the dose and after repeated administration of omeprazole or esomeprazole,the maximal plasma concentration(C max)and area under the concentration-time curve(AUC)increased in a nonlinear fashion[11],which is due to decreased first-pass elimina-tion and decreased systemic clearance(CL).Furthermore, due to a lower metabolic rate of esomeprazole compared with R-or racemic omeprazole,esomeprazole resulted in higher AUC values[11].Similarly,in patients with GERD, the C max and AUC values of esomeprazole increased on day7versus day1by80%and50%,respectively[12].Omeprazole and esomeprazole are extensively metabo-lized by CYP2C19and CYP3A4.Omeprazole is converted mainly to hydroxyl and5-O-desmethyl metabolites by CYP2C19and to the sulfone by CYP3A4[6].In vitro studies suggest that esomeprazole is predominantly metab-olized by CYP3A4and consequently is less dependent on CYP2C19,which recently could be substantiated by a clinical study[13].Approximately80%of each dose is excreted as metabolites in the urine[6].CYP2C19polymorphisms can significantly influence the metabolism of omeprazole and esomeprazole[3,14].Table1Pharmacokinetic properties of proton pump inhibitors(according to Klotz[6])Parameter Omeprazole Esomeprazole Lansoprazole Pantoprazole Rabeprazole t max[h]1–61–3.5 1.2–2.12–43–5F[%]25–40(↑upon multipledosing)50(acute dosing)70–80(chronic dosing)80–907752Linear pharmacokinetics No No Yes Yes Yesfu[%]0.050.050.030.020.04V[l/kg]0.13–0.350.22–0.260.40.15–t1/2[h]0.5–1.20.8–1.30.9–2.10.8–2.00.6–1.4CL[ml/min]400–620330(acute)160–250(chronic)400–65090–225–CL/F[ml/min]320310125600f e[%]Negligible Negligible Negligible Negligible Negligible Effect of age CL↓,t1/2(↑),F↑CL↔,t1/2↔CL↓,t1/2↑CL↔,t1/2↔CL↓,t1/2(↑) Renal insufficiency CL↔,t1/2(↔),F↔–CL↓↔,t1/2↑(↔)CL↔,t1/2↔CL(↑),t1/2↔Hepatic dysfunction CL↓,t1/2↑,F↑CL↓,t1/2↑CL↓,t1/2↑CL↓,t1/2↑,F↔CL↓,t1/2↑t max time to maximal plasma concentration,F oral bioavailability,fu fraction of drug unbound in plasma,V apparent volume of distribution,t1/2 elimination half life,CL systemic clearance,CL/F apparent oral clearance,f e fraction excreted in unchanged form into urine↑increase,↓decrease,↔no significant change,arrows in parentheses effects are equivocalAccording to metabolic rate(phenotype),individuals can be classified as homozygous extensive metabolizers(homEM), heterozygous extensive metabolizers(hetEM)and poor metabolizers(PM).The frequencies of these three sub-groups show a wide interethnic variation.The prevalence of PM ranges from1.2%to3.8%in Caucasian Europeans and up to23%in Asian Oceanian populations[15,16].PMs exhibit a3-to10-fold and hetEMs a2-to3-fold higher AUC(drug exposure)compared with homEMs[3,14].In a recent study,mean AUC ratios of omeprazole were 1:2.7:9.0after a single oral dose of40mg and1:1.7:4.3 after a single i.v.dose of20mg in six homEMs,eight hetEMs,and six PMs,respectively.Therefore,in PMs,F was higher than that in homEMs and hetEMs(87%vs.62% and41%;P<0.001)[17].Similarly,in homEMs,hetEMs, and PMs,the relative AUC ratios were1:2.8:7.5and t1/2 ratios1:1:1.7for omeprazole,indicating that disposition of omeprazole is greatly dependent on the CYP2C19genotype [18].Similar ratios were reported after repeated doses of omeprazole[19].Interestingly,the elderly EMs showed a wide variance in their CYP2C19activity and were phenotypically closer to the PMs than the young EMs compared with the young PMs.Thus,in the elderly,the CYP2C19genotype may not be as useful as phenotyping [20].The most frequently and extensively described variant alleles for PMs are CYP2C19*2and CYP2C19*3,which encode for nonfunctional proteins.Recently,the CYP2C19*17allele has been identified,which is associated with a very rapid metabolism phenotype and has a frequency of18%both in Swedes and Ethiopians but only 4%in Chines populations[21].Such subjects need higher doses of omeprazole for acid suppression[22,23].The pharmacokinetics of omeprazole was compared in 18healthy adults and in12children with GERD(mean age 6.1years).Oral clearance(CL/F)and apparent volume of distribution(V)in healthy adults(0.62L/h per kg and0.76 L/kg,respectively)were not significantly different from those in children with GERD(0.51L/h per kg and 0.66L/kg,respectively).Therefore,dosing on a milligram/ kilogram basis was recommended,with no further adjust-ments for treating GERD in children[24].In27children with GERD aged1–11years,the pharmacokinetic properties of esomeprazole were both dose(between5–20mg)and age dependent.The younger children(1–5years)showed a more rapid metabolism compared with older children(6–11years) [25].In28adolescent patients with GERD aged12–17 years,the mean AUC and C max values of esomeprazole were 3.5-fold higher with the40mg dose compared with the20 mg dose with single-and repeated-dose administration, confirming nonlinear pharmacokinetics[26].All PPIs cause increases in intragastric pH,which can affect absorption of concomitantly given drugs,such as ketoconazole,vitamin B12,and digoxin[27].In addition,omeprazole carries the potential for inhibiting the hepatic elimination of a wide range of drugs,including carbamaze-pine,diazepam,mephenytoin,methotrexate,nifedipine, phenytoin,warfarin,mefloquine,pyrimethamine,and sulfa-doxine[6,27,28].Likewise,inhibitors of CYP2C19or CYP3A4,e.g.,fluconazole[29]and fluvoxamine[30],can affect the metabolism of omeprazole.Furthermore,omepra-zole is a substrate and inhibitor of P-glycoprotein.So drug interactions could be also partly due to an inhibition of P-glycoprotein-mediated drug transport[31,32].On the contrary,St.John’s wort can induce both pathways in the metabolism of omeprazole and decreased its AUC(38–44%) and C max(38–50%)[33].As with smoking,omeprazole can dose dependently induce CYP1A2[6].In general,it can be expected that the interaction potential of esomeprazole is similar to that of racemic omeprazole[27,34].Triple therapy with omeprazole/clarithromycin/amoxicillin is widely used to eradicate H.pylori.The observed pharmacodynamic synergism of these drugs is at least partly due to pharmacokinetic interactions.The AUC of omepra-zole increased almost twofold after concomitant administra-tion of clarithromycin[35].Naproxen and rofecoxib did not interact with esomeprazole and visa versa.Apparently, esomeprazole can be used in combination with NSAIDs without the risk of pharmacokinetic interactions[36].LansoprazoleLansoprazole is rapidly absorbed and displays a linear increase in plasma concentrations over a dose range of15–60mg[37].Pharmacokinetics of repeated doses is similar to that of a single nsoprazole is extensively and rapidly(t1/2:1–2h)metabolized into sulfone and5-hydroxylated metabolites by CYP3A4and CYP2C19.A sulfide metabolite is also present in smaller amounts[6, 37].As CYP2C19is involved in the metabolism of lansoprazole,it is not surprising that PMs have a4.4-fold higher AUC than homEMs[3].The pharmacokinetics of lansoprazole(15mg/day)in children with GERD aged13–24months was comparable to those in older children and adults[38].Fluvoxamine treatment increased AUC of lansoprazole 3.8-fold(P<0.01)in homEMs and2.5-fold(P<0.05)in hetEMs,whereas in PMs,no difference was found in any pharmacokinetic parameter[39].A double-blind,random-ized controlled trial(RCT)showed that clarithromycin treatment significantly increased C max of lansoprazole 1.47-, 1.71-,and 1.52-fold and AUC 1.55-, 1.74-,and 1.80-fold in homEMs,hetEMs,and PMs,respectively. These very similar effects indicate that the drug interactions resulted from inhibition of CYP3A4[40].Surprisingly, grapefruit juice had no significant effect on the pharmaco-kinetics of lansoprazole[41].Lansoprazole did not demonstrate relevant interactions with theophylline,phenytoin,prednisone,warfarin,diaze-pam,oral contraceptives,ivabradine,or methotrexate[37, 42,43].In renal transplant recipients receiving tacrolimus and lansoprazole(30mg)or rabeprazole(20mg),elevated blood concentrations of tacrolimus were observed only in the very rare subgroup of subjects who are PM of CYP2C19and bearing also the CYP3A5*3/*3genotype [44].Absorption of atazanavir was significantly reduced when coadministered with lansoprazole,as evidenced by a 94%decline in AUC and by a96%decrease in C max[45].PantoprazolePantoprazole is rapidly absorbed after oral administration of enteric-coated tablets,which avoid degradation of the PPI by gastric acid[6].It hardly undergoes first-pass metabo-lism and has a bioavailability of approximately77%, independent of dose and food intake.Pantoprazole shows linear pharmacokinetics after both i.v.and oral administra-tion.It is completely metabolized by CYP2C19and CYP3A4.In a major pathway,pantoprazole undergoes O-demethylation followed by sulfate conjugation and sulfone/ sulfide formation[46].Pantoprazole has apparently no clinically relevant drug interactions,other than the class effect associated with elevated intragastric pH.No drug interactions have been demonstrated between pantoprazole and a wide range of drugs,such as theophylline,diazepam, carbamazepine,digoxin,and warfarin[46,47].Unlike omeprazole,administration of clarithromycin did not increase pantoprazole levels[35].RabeprazoleIn healthy subjects,mean F has been calculated to52% [48].C max and AUC values were linearly related to the dose,whereas t max and t1/2were dose independent. Rabeprazole’s metabolism is unique because of its reduc-tion to rabeprazole thioether via a nonenzymatic pathway with renal elimination of the metabolites.Both CYP2C19 and CYP3A4contribute only a small fraction to the overall metabolism[49].Thus,rabeprazole will be less susceptible to the influence of genetic polymorphisms of either CYP2C19or CYP3A4[50].In healthy Chinese subjects, the pharmacokinetics of rabeprazole was dependent to a certain degree on the CYP2C19genotype.AUC values for rabeprazole differed among the three genotype groups (homEM,hetEM,PM),with relative ratios of1.0:1.3:1.8 after a single dose and of1.0:1.1:1.7after repeated doses, respectively.These changes were much smaller than those observed for other PPIs[51].The modest differences in AUC of rabeprazole were also consistent with other studies [18,52].However,in12Chinese subjects receiving rabeprazole20mg b.i.d.,the mean AUC values of rabeprazole and rabeprazole thioether were higher(P< 0.001)in PMs than in EMs on day1.Similar results were observed on day4,which might be due to the high rabeprazole dose(40mg/day)used in this study[53].Pharmacokinetic properties of rabeprazole in children 12–16years old were similar to adults,and during multiple dosing,only headache and nausea were sometimes reported [54].As the CYP450-mediated pathways are secondary in rabeprazole metabolism,it has a low potential for drug interactions involving CYPs.Interaction studies with rabeprazole revealed no significant metabolic effect on theophylline,phenytoin,warfarin,or diazepam[27,49]. Clarithromycin or verapamil did not alter the pharmacoki-netics of rabeprazole,irrespective of the CYP2C19geno-types[55].Interestingly,fluvoxamine,an inhibitor of CYP1A2and CYP2C19,increased AUC of rabeprazole and rabeprazole thioether2.8-and5.1-fold in homEMs and 1.7-and 2.6-fold in hetEMs,respectively,whereas no difference was seen in PMs of CYP2C19[56].According to in vitro experiments all PPIs showed some inhibition of CYP2C9,2C19,and3A4;the inhibitory potency of rabeprazole was relatively lower than that of the other PPIs[57].Pharmacodynamic profileThe primary effect of PPIs is suppression of gastric acid secretion,which will determine healing rates in GERD and PU[58].Intragastric pH monitoring allows direct assess-ment of acid suppression,and it is a very useful measure with which to compare antisecretory therapies[59]. Typically,the antisecretory effects of PPIs have been reported as mean or median24-h intragastric pH or suppression of24-h intragastric acidity expressed as time above a predefined pH threshold.Intragastric pH value above3(PU)and4(GERD)have been defined as therapeutic targets[60].PPIs are regarded to be similarly effective,but their potency differs.Such differences may translate into a slight advantage for a particular PPI in a special clinical situation[61].Onset and degree of acid suppressionAll PPI prodrugs undergo accumulation and acid activation in the parietal cell,which relies on their pK a values.Based on in vitro experiments and pK a considerations,it can be estimated that rabeprazole will show the highest accumu-lation and faster conversion to the active form of the PPIs [1].This might affect the speed of acid suppression by PPIs.Apparently an earlier sustained inhibition of acidsecretion was seen with rabeprazole than with other PPIs [62].Comparing the antisecretory effects on the first day of dosing,rabeprazole achieved better acid control because the intragastric pH(3.4)and the time of pH>4during the 24-h postdose were significantly(P≤0.04)greater with rabeprazole than with lansoprazole,pantoprazole,or two formulations of omeprazole[63].In contrast,in72healthy volunteers,mean24-h pH and percentage of time for pH>4 were not significantly different between lansoprazole30mg and nsoprazole resulted in greater acid suppression during hours0–5on days1and5, whereas rabeprazole had greater suppression during hours 11–24on day5[64].In patients with heartburn,the intragastric pH profiles of all five PPIs were compared after giving once daily esomeprazole40mg,lansoprazole30mg,omeprazole20 mg,pantoprazole40mg,and rabeprazole20mg[65,66]. The results of day5suggest that intragastric pH control with esomeprazole40mg/day was superior to other PPIs [65].Similarly,with the same dosing schedule,esomepra-zole maintained intragastric pH>4for a longer time compared with all other PPIs on days1and5[66].In seven healthy homEMs,the median intragastric pH and percent time pH>4for24h increased dose dependently with omeprazole10,20,and40mg daily for7days,and10 and20mg b.i.d.were comparable with once-daily20and 40mg.Concerning percent time pH>4at nighttime, omeprazole20mg b.i.d.was superior(P<0.05)to40mg daily[67].Three RCTs indicated that a single dose of esomeprazole (40mg i.v.)was superior to omeprazole(40mg i.v.)in reducing stimulated acid secretion.However,control of intragastric pH was similar for esomeprazole and omeprazole at a high dose of80mg(over30min)+8mg/h(for23.5h) [68].Esomeprazole40mg i.v.resulted in11.8h with an intragastric pH>4compared with5.6h(P<0.0001)and 7.2h(P<0.001)for pantoprazole40mg i.v.as infusion or bolus injection,respectively,suggesting that esomeprazole was more potent than pantoprazole[69].Likewise,oral administration of esomeprazole40mg b.i.d.provided better and more consistent intragastric acid control than pantopra-zole40mg b.i.d.[70].In patients with GERD,esomeprazole (40mg daily or b.i.d.)was compared with lansoprazole(30 mg daily or b.i.d.).Mean time pH>4and mean24-h pH were highest for esomeprazole40mg b.i.d.,followed by lansoprazole30mg b.i.d.,esomeprazole40mg once daily, and lansoprazole30mg once daily[71].Based on three pooled open studies in80subjects,single doses of rabeprazole(20mg)and esomeprazole(40mg)were equivalent in their effects on24-h intragastric pH.After5 days’dosing,rabeprazole(20mg)maintained pH>4longer than20mg esomeprazole(62%vs56%;P=0.046),whereas the lower dose(10mg)of rabeprazole was slightly less effective(48%;P=0.035)[72].These results were consistent with two other RCTs[73,74].On a milligram basis,acid inhibition by rabeprazole was significantly superior to omeprazole.After the initial dose, rabeprazole(20mg)inhibited acid secretion by72%after 11h and by64%after23h compared with omeprazole 20mg(49%and38%,P<0.03).This advantage was maintained for8days of treatment[75].In addition,single and multiple doses of rabeprazole20mg produced greater acid suppression than oral or i.v.pantoprazole40mg[76,77].Furthermore,a reduced dose of rabeprazole(10mg b.i.d.)was comparable with the higher dosages of rabeprazole (20mg b.i.d.),to lansoprazole(30mg b.i.d.),and to omeprazole(20mg b.i.d.)for acid-suppressive efficacy [78,79].Overall,pharmacodynamic and clinical data indicated that on a milligram basis,rabeprazole can provide the greatest degree of acid suppression among the available PPIs.It also may provide a faster onset toward a maximal antisecretory effect than other drugs of this class.This can be of therapeutic relevance,as clinical outcome depends on extent and duration of secretory inhibition.Impact of CYP2C19polymorphism on acid suppression PPI-induced inhibition of acid secretion is closely related to AUC values[3,14].As EMs of CYP2C19have smaller AUC values than PMs,the genotype-dependent difference in pharmacokinetics will translate directly into a less pronounced acid suppression in EMs(about70%of Caucasian patients)compared with PMs(see Table2),so that EMs(and carriers of the CYP2C19*17allele)will demonstrate a higher rate of therapeutic nonresponse.This topic has been extensively investigated[80,81].In eight healthy EMs,rabeprazole(10mg/day)showed a faster onset of rising intragastric pH and a stronger inhibition of gastric acid secretion than did lansoprazole (30mg/day)or omeprazole(20mg/day)[82].In nine healthy,H.pylori-negative homEMs treated with rabepra-zole,omeprazole and lansoprazole once daily at reduced Table2Influence of CYP2C19genotype on intragastric pH(accord-ing to Klotz[3])Median pH over24hPPI PM hetEM homEMOmeprazole(20mg for7/8days) 5.7–6.6 4.4–5.5 3.1–4.1 Lansoprazole(30mg for8days) 5.4–6.2 3.5–5.0 3.1–4.5 Rabeprazole(20mg for8days) 5.8–6.0 4.6–5.0 3.8–4.8PPI proton pump inhibitor,PM poor metabolizers,hetEM heterozygous extensive metabolizers,homEM homozygous extensive metabolizersand standard doses for7days,the median values of the 24-h percent of time at pH>4was dose dependent but did not exceed65%under any of the regimens tested.Thus,to achieve effective acid suppression for the initial therapy of GERD,higher doses were needed in homEMs[83].The efficacy of omeprazole(10or20mg for7days)has been shown to be significantly stronger in PMs and hetEMs than in homEMs[84].Likewise,in31Korean patients with GERD receiving omeprazole20mg daily for28days, 24-h intragastric pH in PMs(5.3)was higher(P<0.005) than that in homEMs(2.8)and hetEMs(3.6)[85].In healthy volunteers(six homEMs,nine hetEMs,five PMs) treated with lansoprazole30mg b.i.d.,the median of 24-h intragastric pH in PMs(6.1)was higher(P<0.05)than those in homEMs(4.5)and hetEMs(5.0).In contrast,when lansoprazole30mg b.i.d.was given with famotidine20mg b.i.d.,the median intragastric pH was5.4,5.7,and6.1, respectively.Thus,acid inhibition by lansoprazole was significantly influenced by the CYP2C19genotype,but apparently this genetic influence could be offset by the concomitant use of the H2-receptor antagonist famotidine [86].The impact of the CYP2C19genotype on the efficacy of rabeprazole was less consistent.In H.pylori-negative GERD subjects given rabeprazole10mg/day for8weeks, the intragastric pH elevation was independent of CYP2C19 genotypes[87],which was consistent with another study [52].In contrast,two studies with rabeprazole20or40mg daily for8days demonstrated that acid inhibition by rabeprazole was dependent on the CYP2C19genotype [88,89].In Korean patients,pantoprazole40mg daily exhibited a variable acid inhibition that was significantly dependent on the CYP2C19genotype[90].As there is a significantly positive relationship between the extent and duration of elevated intragastric pH and the clinical efficacy of PPIs,it can be anticipated that the CYP2C19 genotype will have a significant impact on the therapeutic outcome of three PPIs(e.g.,omeprazole,lansoprazole,pantoprazole)that are predominantly metabolized by this polymorphic enzyme.Therapeutic usePeptic ulcerFor the management of PU(healing induction and remission maintenance),both suppression of gastric acid secretion and eradication of H.pylori are important mainstays.In general,there is little overall difference in PU healing rates among PPIs,and reported small differ-ences can be explained best by the variable dosage regimens applied[91–93].H.pylori eradication is accom-plished efficiently(80–90%eradication rates)by standard triple therapy with a PPI,amoxicillin,and clarithromycin or metronidazole[94–96](Table3),and there was no significant difference among the PPIs[97–101].A consensus on the optimal duration(7,10,or14days) of first-line triple therapy is still missing.However,many controlled studies and meta-analyses[102–108]indicated that extending this strategy beyond7days is very unlikely to be clinically useful,especially if taking antibiotic-induced AEs into account[101].There are even some data suggesting that a rabeprazole-based triple therapy for4 days will result in eradication rates around90%[109,110]. More recently,sequential treatment consisting of5days of therapy with a PPI and amoxicillin followed by5days of PPI+clarithromycin and tinidazole has attracted some favorable attention[111–114].As already outlined,the genotype of CYP2C19affects the pharmacokinetics and pharmacodynamics of most PPIs. In a recent meta-analysis of dual and triple therapies a, marked difference in the H.pylori eradication rates between PMs/hetEMs vs.homEMs was calculated,especially for omeprazole[115].Therefore,CYP2C19polymorphism is a major predictor of treatment failure for H.pylori eradication [116,117].Table3Recommendation of Helicobacter pylori eradication formulated in the Maastricht Consensus Report(adapted from Malfertheiner et al.[94])Choice StatementsFirst-choice treatment•PPI-amoxicillin-clarithromycin or metronidazole treatment remains the recommended first-choice treatmentin populations with less than15–20%clarithromycin resistance prevalence.•In populations with less than40%metronidazole resistance prevalence PPI-clarithromycin-metronidazole ispreferable.•Quadruple therapies are alternative first-choice treatments.Second-choice treatment•Bismuth-based quadruple therapies remain the best second-choice treatment.•If not available,a PPI,amoxicillin,or tetracycline and metronidazole are recommended.Third-choice treatment(rescuetreatment)•Rescue treatment should be based on antimicrobial susceptibility testing.。