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`Author Manuscript
`Curr Gastroenterol Rep. Author manuscript; available in PMC 2010 April 15.
`Published in final edited form as:
`Curr Gastroenterol Rep. 2008 December ; 10(6): 528–534.
`
`Pharmacology of Proton Pump Inhibitors
`
`Jai Moo Shin, PhD and George Sachs, DSc, MD
`
`Abstract
`The gastric H,K-ATPase is the primary target for the treatment of acid-related diseases. Proton pump
`inhibitors (PPIs) are weak bases composed of two moieties, a substituted pyridine with a primary
`pKa of about 4.0, which allows selective accumulation in the secretory canaliculus of the parietal
`cell, and a benzimidazole with a second pKa of about 1.0. PPIs are acid-activated prodrugs that
`convert to sulfenic acids or sulfenamides that react covalently with one or more cysteines accessible
`from the luminal surface of the ATPase. Because of covalent binding, their inhibitory effects last
`much longer than their plasma half-life. However, the short half-life of the drug in the blood and the
`requirement for acid activation impair their efficacy in acid suppression, particularly at night. PPIs
`with longer half-life promise to improve acid suppression. All PPIs give excellent healing of peptic
`ulcers and produce good results in reflux esophagitis. PPIs combined with antibiotics eradicate
`Helicobacter pylori.
`
`Introduction
`When activated by stimuli such as histamine and acetylcholine, the parietal cell undergoes
`dramatic morphologic changes from the resting status to the stimulated state. The gastric H,K-
`ATPase, which pumps gastric acid, appears to be in cytoplasmic tubular membranes in the
`resting state and then in the microvilli of the expanded secretory canaliculus in the stimulated
`state of the parietal cell. This morphologic change is proposed to result from fusion of
`cytoplasmic vesicles with the rudimentary microvilli to form the elongated microvilli of the
`expanded secretory canaliculus [1,2]. The gastric H,K-ATPase moves from the tubulovesicles
`to the apical membrane in the canaliculus of the stimulated state and secretes gastric acid by
`an electroneutral, ATP-dependent hydrogen-potassium exchange [3]. The enzyme uses
`extracellular K+ in order to secrete acid by the exchange of cytoplasmic hydronium with this
`K+. The cation reaches the luminal surface of the ATPase by insertion of K+ Cl− (KCNQ1,
`Clic6) channels into the microvillus membrane.
`
`Proton pump inhibitors (PPIs) block the gastric H,K-ATPase, inhibiting gastric acid secretion.
`This effect enables healing of peptic ulcers, gastroesophageal reflux disease (GERD), Barrett’s
`esophagus, and Zollinger-Ellison syndrome, as well as the eradication of Helicobacter pylori
`as part of combination regimens. This article reviews the structure and function of the gastric
`H,K-ATPase and the inhibitors of this enzyme, the PPIs.
`
`The Gastric H,K-ATPase
`The gastric ATPase is a member of the P2 type ATPases. The first step of the reaction is
`phosphorylation of the catalytic subunit by MgATP, with export of protons; this step is
`
`Corresponding author: George Sachs, DSc, MD, Membrane Biology, David Geffen School of Medicine, University of California at Los
`Angeles, Room 324, Building 113, 11301 Wilshire Boulevard, Los Angeles, CA 90073, USA. gsachs@ucla.edu.
`Disclosures
`No potential conflicts of interest relevant to this article were reported.
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`followed by luminal potassium-dependent dephosphorylation and potassium reabsorption. The
`result is electroneutral exchange of cytoplasmic protons for exoplasmic potassium [3]. The
`gastric H,K-ATPase is composed of two subunits: a catalytic α subunit and a β subunit. The
`primary structure of the gastric H,K-ATPase α subunit was elucidated in the rat [4] and then
`in the hog [5], rabbit [6], dog [7], and human [8]. This catalytic subunit consists of 1033 or
`1034 amino acids with 10 transmembrane segments in all species. Functional studies
`demonstrated that ATP catalyzed an electroneutral exchange of H for K, with a variable
`stoichiometry of 2H/2K/ATP at pH 6.1, which fell to 1H/1K/ATP as luminal pH fell below
`3.0 [9–11]. The β subunit consists of 291 amino acids and contains six or seven N-linked
`glycosylation sites with one trans-membrane segment [12–14]. The gastric H,K-ATPase is
`fully assembled during biosynthesis in the endoplasmic reticulum and is delivered to the apical
`membrane as a heterodimeric oligomer. N-glycosylation of the β subunit was identified as
`being responsible for trafficking to the canalicular membrane. The steady state distribution of
`the H,K-ATPase β subunit in polarized cells depends on the balance between direct sorting
`from the trans-Golgi network, secondary associative sorting with a partner protein, and
`selective trafficking [15–17].
`
`In the α subunit, a cluster of intramembranal carboxylic amino acids, located in the middle of
`the transmembrane segments TM4, TM5, TM6, and TM8, contains the ion-binding domain in
`this enzyme, including a lysine 791. This lysine of the H,K-ATPase seems to characterize the
`H,K-enzyme specificity for outward transport of the hydronium ion [18•]. Movement of the
`+ into the carboxylic ion-binding domain is thought to catalyze the export of protons to
`R-NH3
`the luminal face of the pump. The functional form of the gastric H,K-ATPase is a [αβ]2
`heterodimer oligomer [19,20•]. The large changes in conformation in the cytoplasmic domain
`probably account for the finding that the enzyme functions as an out-of-phase oligomeric
`heterodimer, as most clearly demonstrated by measuring the stoichiometry of ATP binding,
`acid-stable phosphorylation, and binding of acid pump antagonists (APAs) or PPIs [20•].
`
`The E1 form of the enzyme allows access to the ion-binding domain from the cytoplasmic
`surface. Binding of two ATP moieties, along with two magnesium ions, occurs in this
`conformation. One stabilizes the αβ orientation of the first two phosphates of the nucleotide,
`and the second, in proximity to the acceptor aspartyl residue, allows transfer of the γ phosphate
`to the catalytic subunit of the protein and initiates the change of conformation from the E1 form
`to the E1P conformer with the ion sites binding the hydronium ions. This process is followed
`by conversion to the E2P form, in which the protons are released outward and K+ binds from
`the luminal surface. ATP has dual roles in the transport cycle of the gastric H,K-ATPase. ATP
`phosphorylates the enzyme and promotes the E2·K→E1 + K+ transition [21]. The potassium
`occlusion site shows distorted octahedral geometry, with K+ bound predominantly on the M4
`helix, with ligands contributed by backbone carbonyl oxygens of V338, A339, and V341, and
`by side chain oxygens of E820 and E795 [18•]. Recently two hydronium transporting pathways
`were proposed [11]. The hydroniums in the binding sites are transported into the lumen during
`the conformational transition from E1P to E2P.
`Chemistry and Biology of PPIs
`Because the H,K-ATPase is the final step of acid secretion, an inhibitor of this enzyme is more
`effective than receptor antagonists in suppressing gastric acid secretion [22]. Timoprazole is
`a compound that inhibited acid secretion in vivo regardless of the nature of the stimulus,
`whether ligands acting via extracellular receptors such as histamine or acetylcholine or the
`intracellular second messenger, cyclic adenosine monophosphate (cAMP). This compound, a
`pyridylmethylsulfinyl benzimidazole, was synthesized in 1975. It was found that the compound
`was ineffective in the absence of acid transport by the ATPase. With acid transport in gastric
`ATPase vesicles, the drug inhibited acid production and ATPase activity. It was therefore an
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`acid-activated prodrug. Omeprazole was subsequently synthesized, and in 1989 it became the
`first drug of this class to be introduced into clinical use. Omeprazole (Losec; AstraZeneca,
`Wilmington, DE) was followed by lansoprazole (Prevacid; TAP Pharmaceuticals, Lake Forest,
`IL), pantoprazole (Protonix; Wyeth Pharmaceuticals, Madison, NJ) or rabeprazole (Aciphex;
`Eisai Company, Woodcliff, NJ) and more recently by the S-enantiomer of omeprazole
`(Nexium, AstraZeneca). Typical structures of PPIs are shown in Figure 1.
`
`PPIs are weak bases with a pKa1 between 3.8 and 4.9. This weak base pKa enables PPIs to
`accumulate selectively in the acidic space of the secretory canaliculus of the stimulated parietal
`cell, where the pH is about 1.0. This acid space–dependent concentration of PPIs is the first
`important property that determines their therapeutic index, giving a concentration at the luminal
`surface of the pump that is about 1000-fold higher than in the blood. The second step is acid-
`dependent conversion from the accumulated prodrug to the activated species, which is a highly
`reactive thiophilic reagent. A second protonation of these compounds is required for their
`activation to the compounds that form disulfides with luminally accessible cysteines of the
`H,K-ATPase. The actual inhibitory form of these prodrugs is a tetracyclic sulfenamide or
`sulfenic acid. The order of acid stability is tenatoprazole > pantoprazole > omeprazole >
`lansoprazole > rabeprazole [23].
`
`Depending on the difference of the substituents on the pyridine or benzimidazole, PPIs bind
`to different cysteines. Omeprazole binds at cysteine 813 and cysteine 892. Lansoprazole binds
`at cysteine 813 and cysteine 321. Pantoprazole and tenatoprazole bind at cysteine 813 and
`cysteine 822. With acid transport by the ATPase, the second proton is added and then the
`compound converts to the sulfenic acid. If this occurs rapidly, as for omeprazole or
`lansoprazole, reaction with cysteine 813 and/or cysteine 321 takes place, and no drug can access
`cysteine 822. However, if the activation is delayed, the drug can access cysteine 822 before
`activation to the sulfenic acid. Then, when activated, both cysteine 813 and 822 are derivatized,
`as found for pantoprazole or tenatoprazole [23–27].
`
`Differences of PPI binding sites modify biologic activity. When the PPI-bound enzyme was
`treated with glutathione, an endogenous reducing agent with a concentration of about 3 mM
`in the parietal cell, omeprazole and pantoprazole differed in loss of PPI binding. Pantoprazole
`binding resists glutathione reduction. These observations suggest that removal of binding of
`the drug to cysteine 813 accounts for the fast phase of recovery of acid secretion; the slow
`recovery occurs because of a delay in removal of the drug from cysteine 822. Both residues,
`cysteine 813 and 822, are equally labeled by pantoprazole in vivo. The small amount of cysteine
`822 bound by omeprazole in vivo is not seen in vitro [26,28], presumably because acidification
`in isolated gastric vesicles is less than occurs in vivo. In vivo, it is likely that a minor fraction
`of the omeprazole remains protonated at both the pyridine and benzimidazole nitrogen and is
`slowly activated, allowing some access to cysteine 822.
`
`Efficacy of Inhibition of Acid Secretion
`All of these drugs inhibit the gastric H,K-ATPase by covalent binding, so the duration of their
`effect is longer than expected from their levels in the blood [28]. However, PPIs cannot inhibit
`all gastric acid pumps with oral dosing because not all pumps are active during the 90-minute
`half-life of the PPI in the blood. Because PPIs have a short half-life, only 70% of the pump
`enzymes are inhibited. It takes about 2 to 3 days to reach steady state inhibition of acid secretion.
`The pump protein has a half-life of about 54 hours in the rat [29] (and probably in humans).
`Thus about 20% of pumps are newly synthesized over a 24-hour period, and there may be
`greater pump synthesis at night than during the day. In addition, bedtime administration of
`PPIs will not add to inhibition of nocturnal acid breakthrough, because the drug will have
`disappeared by the time nighttime acid secretion is evident. Assuming that about 70% of pumps
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`are activated by breakfast and that the PPI is given 30 to 60 minutes beforehand, it can be
`calculated that steady state inhibition on once-a-day dosing is about 66% of maximal acid
`output. Increasing the dose has virtually no effect once optimal dosage has been reached.
`Increasing the dose frequency does have some effect; a morning dose and an evening dose
`before meals results in about 80% inhibition of maximal acid output.
`
`To improve acid inhibition, the plasma half-life of the PPI must be increased. One means is to
`replace the benzimidazole with imidazopyridine, slowing metabolism and prolonging the half-
`life of the drug, as found with tenatoprazole [30]. This PPI has an advantage in suppressing
`nighttime acid secretion, but its slow activation blunts its advantage for daytime acid
`suppression. An alternative approach was to synthesize a slowly absorbed derivative of
`omeprazole, which then increased the plasma half-life about threefold and produced a median
`pH of about 5 in initial studies [30].
`
`Stability of Inhibition of Acid Secretion
`Reversal of inhibition of the ATPase can occur either by de novo synthesis or reduction of the
`disulfide bond between the PPI and the protein. A rationale for examination of reversal of
`covalent binding to the H,K-ATPase was provided by measurement of the half-life of pump
`protein biosynthesis in rats treated for 7 days with omeprazole, which was 54 hours, and the
`half-time of restoration of ATPase activity, 15 hours. Such data suggest a more rapid recovery
`of ATPase activity and acid secretion than would occur if only de novo biosynthesis was
`responsible for restoration of ATPase activity [29]. In other experiments, the halftime of
`restoration of acid secretion in omeprazole-treated rats was 20 hours [31,32]. An analysis of
`the rate of restoration of acid secretion in humans suggested that the half-time was 24 hours
`following omeprazole inhibition, whereas after pantoprazole it was 46 hours [33]. Only
`pantoprazole appears to have a rate of recovery compatible with restoration of acid secretion
`due entirely to pump turnover [34,35].
`
`Clinical Pharmacology of PPIs
`In healthy humans, the half-life of PPIs is about 1 hour (9 hours for tenatoprazole), but the
`duration of acid inhibition is 48 hours because of irreversible binding to the H,K-ATPase. The
`maximal plasma drug concentration (Cmax) and the degree of acid suppression are poorly
`correlated, but the area under the plasma concentration–time curve (AUC) correlates well with
`acid suppression. Some pharmacokinetic parameters of the PPIs are summarized in Table 1.
`
`The oral bioavailability of PPIs is high: 77% for pantoprazole, 80% to 90% for lansoprazole,
`and 89% for esomeprazole, for example [36–39].
`
`All the PPIs except tenatoprazole are rapidly metabolized in the liver by CYP enzymes (mostly
`by CYP2C19 and 3A4). Because of the sensitivity of PPIs to CYP enzymes, the
`pharmacokinetic profiles of PPIs are very different depending on the phenotypes of the
`metabolizers. Three phenotypes have been identified in various populations: extensive
`metabolizers (homEM), poor metabolizers (PM), and individuals carrying one wild-type and
`one mutant allele (hetEM). Poor metabolizers make up 3% of Caucasians and 15% to 20% of
`Asians. Systemic drug exposure (AUC) varies widely between these three populations: the
`AUC for omeprazole is about 7.5-fold higher in PM than in homEM, about 4.5-fold higher for
`lansoprazole, and about fourfold higher for rabeprazole. Because the pharmacodynamic
`response to PPIs is related to their AUC, intragastric pH is more elevated in PM (median pH
`~6) and hetEM (median pH ~4–5) than in homEM (median pH ~3–4) [40]. Patients with hepatic
`impairment show a sevenfold increase in AUC for PPIs and a prolonged half-life.
`Esomeprazole was well tolerated across the spectrum of hepatic impairment, unlike other PPIs
`[41].
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`Comparing the Efficacy of PPIs
`Suppressing gastric acid secretion enhances healing of acid-related diseases. Good healing of
`reflux esophagitis is achieved when the intragastric pH is greater than 4 for 16 hours per day,
`and peptic ulcer is optimally healed when the intragastric pH is greater than 3 for 16 hours per
`day. [42]. The best in vivo parameters to use in comparing PPIs with each other are the
`intragastric pH and total acid output. Generally, all PPIs provide good gastric acid suppression,
`but because they are used at different doses (omeprazole 20 mg, lansoprazole 30 mg,
`pantoprazole 40 mg, rabeprazole 20 mg, esomeprazole 40 mg, and tenatoprazole 40 mg), it is
`not easy to compare their efficacy.
`
`One study compared rabeprazole (20 mg), lansoprazole (30 mg), pantoprazole (40 mg), and
`omeprazole (20-mg capsule vs 20-mg multiple unit pellet system tablet) [43]. Rabeprazole had
`the highest first-day median 24-hour pH. Another study compared gastric acid inhibition
`following the administration (30 minutes before breakfast) of rabeprazole (20 mg),
`esomeprazole (40 mg), omeprazole (20 mg), lansoprazole (30 mg) and pantoprazole (40 mg)
`for 5 consecutive days. At the end of the 5-day period, intragastric pH greater than 4 was
`maintained longer with esomeprazole, and more patients had a pH greater than 4 for more than
`12 hours [44]. Esomeprazole (40 mg) gives good acid suppression (pH > 4 for 16.8 h/d) [45].
`
`When lansoprazole (30 mg) was compared with omeprazole (20 mg), both taken orally on a
`daily basis, lansoprazole maintained the pH > 3 for a significantly greater time and produced
`a higher median 24-hour pH [46,47]. However, many other studies comparing omeprazole and
`lansoprazole have shown no significant difference overall in any pH parameters [48,49].
`Pantoprazole (40 mg) has also been compared with omeprazole (20 mg); the results showed a
`significantly higher daytime and 24-hour pH with pantoprazole [50]. When the efficacy of each
`PPI is compared based on same dose, omeprazole, lansoprazole, and pantoprazole seem to
`produce similar acid suppression.
`
`Tenatoprazole (40 mg) provided better nighttime acid suppression than other PPIs [51]. A
`significant difference was observed between tenatoprazole and esomeprazole during the
`nocturnal period; the mean pH was 4.64 with tenatoprazole versus 3.61 with esomeprazole,
`and the mean percentage of time with pH greater than 4 was significantly higher for
`tenatoprazole [52]. This difference is due to the prolonged half-life of tenatoprazole in the
`blood.
`
`Many studies have compared healing rates of GERD. In comparisons of lansoprazole (30 mg)
`with omeprazole (20 mg), there was no significant difference in endoscopic healing rates at 4
`and 8 weeks [53–55]. Again, when lansoprazole (30 mg) was compared with omeprazole (40
`mg), no significant differences were found in healing rates or relief of symptoms [56].
`Rabeprazole (20 mg) and omeprazole (20 mg) produced equivalent healing rates and relief of
`symptoms at 4 and 8 weeks [57].
`
`More GERD patients (93.7%–94.1%) were healed at week 8 with the use of 40 mg of
`esomeprazole than with 20 mg of omeprazole (84.2%–86.9%) [58,59]. When 40 mg of
`esomeprazole was compared with 40 mg of pantoprazole, both gave good healing rates [60].
`
`PPIs have been used successfully in triple-therapy regimens with clarithromycin and
`amoxicillin for the eradication of H. pylori. There was no significant difference between
`different PPI-based regimens.
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`Conclusions
`The PPIs are prodrugs. These prodrugs require gastric acid secretion to be converted to the
`active sulfenamide or sulfenic acid that blocks gastric acid secretion. All PPIs except
`tenatoprazole have short half-lives (about 1 hour) and all have good oral bioavailability. Most
`PPIs are metabolized by CYP2C19 and 3A4. Hepatic impairment and old age reduce clearance
`of the PPIs, as do mutations in CYP2C19.
`
`Acid suppression studies comparing omeprazole, lansoprazole, rabeprazole, and pantoprazole
`show equivalent efficacy. Most studies using standard doses have not shown a significant
`difference between the four PPIs for the healing of reflux esophagitis or duodenal ulcer.
`Esomeprazole and tenatoprazole have stronger acid suppression, with a longer period of
`intragastric pH greater than 4.
`
`Acknowledgments
`This work was supported by a US Veterans Administration Merit Grant and grants DK053642 and DK58333 from
`the National Institute of Diabetes and Digestive and Kidney Diseases.
`
`References and Recommended Reading
`Papers of particular interest, published recently, have been highlighted as:
`
`• Of importance
`
`•• Of major importance
`
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`17. Vagin O, Turdikulova S, Yakubov I, et al. Use of the H,K-ATPase beta subunit to identify multiple
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`18•. Munson K, Law RJ, Sachs G. Analysis of the gastric H,K ATPase for ion pathways and inhibitor
`binding sites. Biochemistry 2007;46:5398–5417. This study showed how potassium ion moves
`across the membrane in the gastric H,K-ATPase. The new E2P model had increased separation
`between transmembrane segments M3 through M8, and addition of water in this space showed not
`only an inhibitor entry path to the luminal vestibule but also a channel leading to the ion binding
`site. Addition of K+ to the hydrated channel with molecular dynamics modeling of ion movement
`identified a pathway for K+ from the lumen to the ion binding site to give E2K. Autodock analyses
`of the new E2P model now correctly discriminate between high-affinity and low-affinity K+
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`demonstrated that the gastric H,K-ATPase is an oligomeric structure composed of E1:E2. At < 10
`μM MgATP, E1[ATP]·Mg·(H+):E2 is formed at a high-affinity site converting to E1P·Mg· (H
`+):E2 then to E2P·Mg:E1 with luminal proton extrusion. At high MgATP (> 0.1 mM), the oligomer
`forms E2P·Mg:E1[ATP]·Mg·(H+). The sum of maximal EP formation and ATP binding was 5.3
`nmol/mg. An inhibitor, INT bound at the enzyme with 2.6 nmol/mg in the presence of MgATP.
`Binding of the inhibitor fixes half the oligomer in the E2 form with full inhibition of activity, whereas
`the other half of the oligomer is able to form E1P only when the inhibitor is bound. It appears that
`the catalytic subunits of the oligomer during turnover in intact gastric vesicles are restricted to a
`reciprocal E1:E2 configuration. [PubMed: 16331993]
`21. Reenstra WW, Crothers J Jr, Forte JG. The conformation of H,K-ATPase determines the nucleoside
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`blocking (H+ + K+)ATPase. Nature 1981;290:159–161. [PubMed: 6259537]
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`on the gastric H+,K+-ATPase in vitro and in vivo. Biochem Pharmacol 2006;71:837–849. [PubMed:
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