potassium-competitive acid blockade: a new therapeutic...
TRANSCRIPT
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www.elsevier.com/locate/pharmthera
Pharmacology & Therapeutic
Associate editor: G.J. Sanger
Potassium-competitive acid blockade: a new therapeutic
strategy in acid-related diseases
Kjell Andersson *, Enar Carlsson
AstraZeneca R&D, 431 83 Mölndal, Sweden
Abstract
Current therapies to treat gastroesophageal reflux disease (GERD), peptic ulcer disease (PUD), and other acid-related diseases either
prevent stimulation of the parietal cell (H2 receptor antagonists, H2RAs) or inhibit gastric H+,K+-ATPase (e.g., proton pump inhibitors, PPIs).
Of the 2 approaches, the inhibition of the final step in acid production by PPIs provides more effective relief of symptoms and healing.
Despite the documented efficacy of the PPIs, therapeutic doses have a gradual onset of effect and do not provide complete symptom relief in
all patients. There is scope for further improvements in acid suppressive therapy to maximize healing and offer more complete symptom
relief. It is unlikely that cholecystokinin2 (CCK2, gastrin) receptor antagonists, a class in clinical trials, will be superior to H2RAs or PPIs.
However, a new class of acid suppressant, the potassium-competitive acid blockers (P-CABs), is undergoing clinical trials in GERD and
other acid-related diseases. These drugs block gastric H+,K+-ATPase by reversible and K+-competitive ionic binding. After oral doses,
P-CABs rapidly achieve high plasma concentrations and have linear, dose-dependent pharmacokinetics. The pharmacodynamic properties
reflect the pharmacokinetics of this group (i.e., the effect on acid secretion is correlated with plasma concentrations). These agents dose
dependently inhibit gastric acid secretion with a fast onset of action and have similar effects after single and repeated doses (i.e., full effect
from the first dose). Animal studies comparing P-CABs with PPIs suggest some important pharmacodynamic differences (e.g., faster and
better control of 24-hr intragastric acidity). Studies in humans comparing PPIs with P-CABs will help to define the place of this new class in
the management of acid-related diseases.
D 2005 Elsevier Inc. All rights reserved.
Keywords: Gastroesophageal reflux; Peptic ulcer disease; Potassium-competitive acid blocker; Proton pump inhibitor
Abbreviations: CCK, cholecystokinin; cyclic AMP, cyclic adenosine monophosphate; ECL, enterochromaffin-like cell; GERD, gastroesophageal reflux
disease; H2RA, histamine H2 receptor antagonist; P-CAB, potassium-competitive acid blocker; PPI, proton pump inhibitor.
Contents
0163-7258/$ - see fro
doi:10.1016/j.pharmth
* Corresponding aut
E-mail address: k
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 295
2. Physiology of acid secretion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 295
3. Structure and properties of gastric H+,K+-ATPase . . . . . . . . . . . . . . . . . . 296
4. Targeting gastric acid secretion . . . . . . . . . . . . . . . . . . . . . . . . . . . 296
4.1. H2 receptor antagonists and H3 receptor agonists . . . . . . . . . . . . . . 297
4.2. Muscarinics and cholecystokinin2 receptor antagonists . . . . . . . . . . . . 297
4.3. Proton pump inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . 297
5. Potassium-competitive acid blockers. . . . . . . . . . . . . . . . . . . . . . . . . 299
5.1. Development of the potassium-competitive acid blocker class . . . . . . . . 299
5.2. Mechanism of potassium-competitive acid blocker inhibition of gastric
H+,K+-ATPase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 300
5.3. Selectivity of potassium-competitive acid blockers for gastric H+,K+-ATPase . 301
nt matter D 2005 Elsevier Inc. All rights reserved.
era.2005.05.005
hor. Integrative Pharmacology, AstraZeneca R&D, Mölndal, Sweden.
[email protected] (K. Andersson).
s 108 (2005) 294 – 307
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K. Andersson, E. Carlsson / Pharmacology & Therapeutics 108 (2005) 294–307 295
5.4. Pharmacokinetics of potassium-competitive acid blockers . . . . . . . . . . 301
5.5. Pharmacodynamics of potassium-competitive acid blockers . . . . . . . . . 302
5.6. Pharmacodynamic comparisons of potassium-competitive acid blockers with
other agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 302
6. Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 303
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 303
1. Introduction
By the 19th century, gastric acid was known to be
important in many physiological processes, such as protein
digestion and the absorption of calcium and iron. Alongside
these functions, sterilization of food is now also recognized
as a vital function of gastric acid. Over time, awareness of
its central role in the etiology of peptic ulcer disease (PUD),
and more recently, gastroesophageal reflux disease (GERD),
has also grown. This knowledge, together with an increased
understanding of the physiology of acid production, directed
the search for therapies in these diseases through inhibition
of gastric acid secretion. However, until just under 30 years
ago, patients with acid-related diseases had to rely on
antacids, atropine, and other interventions (e.g., behavioral)
for the relief of symptoms. The treatment of PUD was
challenging and, apart from surgery, employed largely
ineffective approaches that included a bland diet, antacids,
and anticholinergics. Although antacids, and other
approaches such as dietary changes and sucralfate, provide
a degree of relief from the symptoms of GERD, healing of
erosions was very difficult to achieve except with high and
frequent doses of antacids (Grove et al., 1985).
The emergence of H2 receptor antagonists (H2RAs) in
the 1970s represented the first major advance in the
treatment of GERD and PUD, as they provided better
symptom control and allowed higher healing rates
compared with antacids. However, these agents have a
relatively short duration of action, their effect is dimin-
ished by meal-stimulated secretion, and tolerance to their
antisecretory effect can develop. Other approaches used to
treat GERD (e.g., prokinetics, sucralfate) have generally
not met expectations.
The first proton pump inhibitor (PPI), omeprazole, was
approved for use in 1988 (Lindberg et al., 1990) and was the
forerunner of a more effective class of agents than H2RAs.
PPIs provide superior symptom relief and achieve higher
healing rates in GERD and PUD than do H2RAs (Chiba et
al., 1997; van Pinxteren et al., 2001; Salas et al., 2002).
Despite the undoubted efficacy of PPIs, there are still areas
in which they could be improved upon (e.g., faster and
better symptom control and more rapid healing). The quest
for better therapy has driven research into other acid-
suppressive treatments. This review examines the develop-
ment and properties of current and potential treatments to
suppress acid production, with particular emphasis on the
potassium-competitive acid blocker (P-CAB) class.
2. Physiology of acid secretion
Hydrochloric acid (HCl) is secreted into the lumen of the
stomach by parietal cells in the glands of the oxyntic
mucosa. Gastric H+,K+-ATPase is fundamental to this
process of acid secretion. This enzyme, located in the apical
membrane of the parietal cell, transports H+ into the parietal
cell canaliculus in exchange for K+. The secretion of H+ is
accompanied by the passage of Cl� across the apical
membrane into the canaliculus, which ensures that acid
secretion is electroneutral. For each H+ ion that is moved
into the canaliculus by the action of the H+,K+-ATPase, a
HCO3� ion is moved out of the parietal cell cytoplasm by a
basolateral Cl�/HCO3� exchanger that also delivers a Cl�
ion into the cytosol. Cl� is secreted into the canaliculus via
Cl� channels in the apical membrane of the parietal cell. It is
possible that more than 1 type of Cl� channel is involved in
the movement of Cl� across the membrane, but currently,
there is evidence only for the ClC-2 channel (Malinowska et
al., 1995).
The exchange of H+ for K+ requires a relatively high
level of K+ in the parietal cell canaliculus. There is evidence
that K+ transported into the cytoplasm by the enzyme is
recycled and returns to the canaliculus via specific K+
channels in the apical membrane of the cell. To date, 3
different types of K+ channels (KCNQ1, Kir2.1, and Kir4.1)
with properties consistent with a role in acid secretion have
been identified in animals (Dedek & Waldegger, 2001;
Grahammer et al., 2001; Fujita et al., 2002; Lambrecht et al.,
2004; Malinowska et al., 2004). It is uncertain what the
counterpart(s) of these channels may be in humans.
Production of gastric acid by the parietal cell is a tightly
regulated process and is triggered by physiological stim-
ulation of receptors located on the basolateral membrane of
the cell. The stimuli include histamine, gastrin, and
acetylcholine, each of which binds to a specific receptor.
This ligand–receptor interaction involves an elevation of
intracellular calcium and/or cyclic adenosine monophos-
phate (cyclic AMP) as part of the signal transduction
pathways. Activation of these pathways result in morpho-
logical and ultrastructural changes that lead to the inclusion
of the gastric H+,K+-ATPase into the apical membrane of the
cell and, ultimately, acid secretion.
In the cytoplasmic space of the unstimulated parietal cell
are tubulovesicles, which contain the gastric H+,K+-ATPase.
The apical membrane of the parietal cell has canaliculi that
invaginate from its surface and in the resting cell that are
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K. Andersson, E. Carlsson / Pharmacology & Therapeutics 108 (2005) 294–307296
lined with short microvilli. When the cell is stimulated, the
microvilli on the apical membrane elongate, the canalicular
spaces enlarge, and the number of tubulovesicles decreases.
It is generally agreed that the tubulovesicular membrane
fuses with the apical plasma membrane (Forte & Yao, 1996;
Duman et al., 2002). Prior to stimulation of the cell, the
H+,K+-ATPase is inactive due to the low permeability of the
tubulovesicular membranes to K+ (Reenstra & Forte, 1990).
The enzyme does not appear to undergo any chemical
modification on membrane fusion (Dunbar & Caplan,
2001), but its consequent placement near to K+ and Cl�
channels, together with the availability of K+ in the
canaliculus, provides the necessary environment to allow
ATP-driven secretion of HCl (Forte & Yao, 1996).
The concentration of H+ in the parietal cell canaliculi
results in a pH of 1.0 or less, compared with a pH of 7.4 in
the blood and parietal cell cytoplasm. To be able to create
such a pH gradient requires a lot of energy (e.g., ATP),
hence the parietal cell is the most mitochondria-rich cell in
the body. The pH in the canaliculi is much lower than that in
other acidic compartments such as lysosomes, endosomes,
and chromaffin granules. In these locations, the pH ranges
from 4.5 to 6.5 (Futai et al., 2000). Gastric H+,K+-ATPase
has been suggested to be present at sites other than the
stomach (e.g., the cortical collecting duct of the kidney;
[Kraut et al., 2001], rat vascular smooth muscle cells
[McCabe & Young, 1992], human leucocytes [Ritter et al.,
1998], and rat cardiac myocytes [Beisvag et al., 2003]). The
enzymes at these locations do not generate a very low pH,
but probably contribute to acid–base and potassium homeo-
stasis (van Driel & Callaghan, 1995; Sangan et al., 1997;
Kraut et al., 2001). Other H+,K+-ATPase isoforms have been
reported to occur in various cells (e.g., in the colon;
Rajendran et al., 1998). For a discussion of the selectivity
of P-CABs for gastric H+,K+-ATPase, see Section 5.3.
3. Structure and properties of gastric H+,K+-ATPase
The gastric H+,K+-ATPase is an a/h heterodimer, witheach subunit having distinct functions. The a subunit, whichhas 10 helical transmembrane segments (M1–M10), is
responsible for the catalytic activity of the enzyme and
contains sites for ATP binding, as well as the cation (K+ and
H+) binding site. The latter binding site is located near the
middle of the membrane domains in the a subunit (Munsonet al., 2000). It appears to be formed by amino acid residues
from M4, M5, and M6, with the ion being held in place by 6
oxygen atoms provided by these residues (Koenderink et al.,
2004). The h subunit has a single transmembrane domain.The subunit is required for the functional expression of the
enzyme.
The exchange of H+ for K+ involves conformational
changes in the tertiary structure of gastric H+,K+-ATPase
(Vander Stricht et al., 2001). According to the Post-Albers
model, there are 2 important conformational states. In the E1
form, the ion-binding site faces the parietal cell cytoplasm
and has high affinity for H+ but low affinity for K+. In the E2form, the ion-binding site faces the extracellular lumen with
low affinity for H+ and high affinity for K+. The relative
affinity of the 2 forms for K+ may be determined by
differences between the E1 and E2 forms in the topography
of the K+ ion binding site or in the path through which the
ion accesses its binding site (Vagin et al., 2003). The K+
affinity is also influenced by a salt bridge from M5 to M6
that exists only when the enzyme is in the E2 form
(Koenderink et al., 2004).
H+ binds to the cytoplasmic face of the enzyme when it
is in the E1 form. The E1 form also binds ATP from the
cytoplasm to form a phosphoenzyme (E1P), which
provides the energy for the change to the (phosphorylated)
E2 form of the enzyme. The conformational shift causes
the translocation of H+ from the parietal cell cytoplasm
into the canaliculus. The phosphorylated E2 form binds K+
from the canaliculus. This ion is necessary for the
subsequent dephosphorylation of the H+,K+-ATPase
(Rabon et al., 1993). In particular, K+ appears to affect
the conformation of a large loop in which there is a
phosphorylation domain, and it is involved in stabilizing a
hairpin between M5 and M6 that appears to be involved in
linking ATP hydrolysis to cation transport (Swarts et al.,
1998; Gatto et al., 1999). When K+ occupies the cation
binding site, it may activate the enzyme by neutralizing a
negative charge (or charges) that inhibit the dephosphor-
ylation reaction (Swarts et al., 1998; Hermsen et al., 2000).
Upon dephosphorylation, the conformation of the enzyme
returns to the E1 form in which the binding site is again
exposed to the cytoplasm. The enzyme then releases K+
into the parietal cell cytoplasm. Thus, K+ is not only the
counterion for H+, but is also essential for the catalytic
cycle of gastric H+,K+-ATPase.
4. Targeting gastric acid secretion
The treatment of peptic ulcer disease (PUD) has been
based on Karl Schwartz’s dictum of Fno acid, no ulcer_.Although recent advances in our understanding have high-
lighted the multifactorial pathogenesis of both PUD and
GERD, gastric acid is still recognized as a central
component in both diseases. There is a correlation between
healing of GERD lesions and the proportion of time (over
24 hr) when intragastric pH is greater than 4 (Bell et al.,
1992). Furthermore, the period during which esophageal pH
is less than 4 increases on moving from endoscopy-negative
GERD patients to patients with worsening grades of
esophagitis (Fiorucci et al., 1992). Therapeutically, the
degree of acid suppression and its relationship with a
positive outcome (e.g., symptom relief, healing) has been
documented both for GERD and PUD (Howden et al., 1994;
Chiba et al., 1997; Selby et al., 2000; van Pinxteren et al.,
2003).
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K. Andersson, E. Carlsson / Pharmacology & Therapeutics 108 (2005) 294–307 297
The groundwork for the current therapeutic approaches
to controlling gastric acid production was laid in the 19th
century. Through the work of many scientists (e.g., Prout,
Gunzberg, Beaumont, Heidenhain, and Cooper), the phys-
iology of gastric secretion and the pathophysiology of PUD
have been increasingly elucidated. There has also been an
increasing understanding of the role of gastric acid in
GERD. By the mid-20th century, this growing knowledge
led to several pharmaceutical companies (e.g., SmithKline
& French, Servier, Searle, and Astra) developing drugs to
inhibit the production of gastric acid.
4.1. H2 receptor antagonists and H3 receptor agonists
The development of H2RAs can be traced back to the
early 1960s when Sir James Black and his colleagues at
SmithKline & French embarked on a research program to
identify histamine receptors. This work resulted in the
development of burimamide, the first selective antagonist of
the H2 receptor. Burimamide was the lead compound in a
search for more potent antagonists. It was tested in humans
but was not sufficiently active by the oral route to be
developed as a medicine. Chemical modifications and
subsequent screening led to the development of cimetidine.
This H2RAwas approved in 1976 in the UK and in 1977 in
the USA and was the progenitor of a group of compounds
that has been recognized as a breakthrough in the treatment
of PUD and GERD.
H2RAs are more effective than antacids at providing
symptom relief and lesion healing in both PUD and GERD.
However, these compounds have a relatively short duration
of effect and their effects are mitigated by food ingestion. A
further limitation is that tolerance can develop after a few
days of continuous dosing, a clinically relevant phenom-
enon in some patients (Lachman & Howden, 2000;
Komazawa et al., 2003).
The work of Black and colleagues caused a resurgence of
interest in histamine, and a third histamine receptor, H3, has
since been discovered. This receptor is detected in the
peripheral and central nervous system and in several
nonneural tissues (Barocelli & Ballabeni, 2003). Centrally
located H3 receptors probably contribute to the regulation of
acid secretion and inhibit cholinergic-stimulated acid
production. The H3 receptor agonist R(a)-methylhistaminehas had variable and contradictory effects on gastric acid
secretion in vitro and in vivo (Barocelli & Ballabeni, 2003).
Thus, it is difficult to predict whether this or other agents
will be effective treatments for acid-related diseases.
Currently, there does not appear to be an H3 receptor
agonist in clinical development for the treatment of gastric
acid-related diseases.
4.2. Muscarinics and cholecystokinin2 receptor antagonists
Other stimulatory pathways in gastric acid secretion have
been the focus of approaches to block acid production; they
include muscarinic (M3) and cholecystokinin2 (CCK2,
gastrin) receptor antagonists. There are currently no M3-
specific antagonists available in the clinical setting for the
treatment of acid-related diseases. However, anticholinergic
agents (e.g., pirenzepine, telenzepine, and atropine) have a
long history in the treatment of PUD (Eltze et al., 1985;
Fiorucci et al., 1988), but as they inhibit M1 receptors at
locations outside the stomach, they are associated with
anticholinergic side effects that limit their use.
The development of the CCK2 antagonists has been
reviewed by Black and Kalindjian (2002). Acting via CCK2receptors, gastrin mediates acid secretion primarily by
causing release of histamine from enterochromaffin-like
(ECL) cells and also, at least in vitro, by directly stimulating
parietal cells (Kopin et al., 1992; Cabero et al., 1993; Prinz
et al., 1993, 1994). A number of CCK2 receptor antagonists
have been evaluated and shown to reduce acid secretion
(YF476 [Steel, 2002], YM022 [Nishida et al., 1994],
RP73870 [Pendley et al., 1995], spiroglumide [Beltinger
et al., 1999], and S0509 [Takeuchi et al., 1999]), but their
development has been discontinued.
Two CCK2 receptor antagonists in clinical studies
include Z360 and itriglumide (Vakil, 2004). Z360 is in
early clinical development for reflux esophagitis and gastric
ulcer. In preclinical studies, Z360 was more potent than
famotidine at inhibiting pentagastrin-stimulated acid secre-
tion and also reduced meal-induced acid production in rats
and dogs (Miura et al., 2001; Morita et al., 2001). The status
of itriglumide is uncertain: Phase I clinical studies on
gastrin- and meal-induced gastric secretion were reported to
be in progress, and Phase II clinical studies in peptic ulcer
were scheduled to be complete by the end of 2003
(Rottapharm, 2004). In pentagastrin-stimulated rats, itriglu-
mide was less potent than ranitidine or omeprazole when
administered intravenously, but intraduodenally, it was 3
times more potent than ranitidine and twice as potent as
omeprazole (Makovec et al., 1999).
It is unlikely that there will be a role for CCK2antagonists alone as alternative antisecretory therapy to
PPIs or H2RAs, especially given the development of
tolerance with at least 1 member of this class (i.e., YF476;
Black & Kalindjian, 2002; Steel, 2002).
4.3. Proton pump inhibitors
One of several companies that started up research
programs with the intention of developing a drug that
would reduce gastric acid secretion was Hässle (a
research unit within AB Astra, Sweden). The initial idea
was to find a drug to inhibit the release of gastrin but the
approach was not successful. However in 1971 the French
company Servier reported (Malen & Danree, 1971) that
the compound CMN 131 (a gastrin receptor antagonist)
inhibited acid secretion but resulted in acute toxicity in
animals. The thioamide group of this compound was
assumed to be responsible for its toxicity, and therefore
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Fig. 1. Mode of action of a PPI. PPIs are weak bases that concentrate in the
parietal cell canaliculus, where they undergo a proton-catalyzed, 3-step
process to generate the active sulfenamide. This moiety interacts covalently
with sulfhydryl groups on cysteine residues in the transmembrane domains
of the gastric H+,K+-ATPase and thereby inhibits the enzyme.
K. Andersson, E. Carlsson / Pharmacology & Therapeutics 108 (2005) 294–307298
this group was eliminated by incorporating it into or
between heterocyclic ring systems. Based on this strategy,
substituted benzimidazoles with potent antisecretory prop-
erties but without acute toxicity were identified. A
number of such compounds (H124/26, timoprazole, and
picoprazole) were selected as candidate drugs during the
1970s, but all were associated with safety problems in
long-term toxicity studies. The breakthrough came with
the synthesis of omeprazole in 1979. This compound was
the most potent of a series of candidate drugs synthesized
and tested, and it did not show any significant effects in
the initial repeat-dose toxicity studies in animals. Thus,
the project started with a lead compound CMN 131, a
gastrin receptor antagonist, and ended with the discovery
of a complete new mechanism of action: inhibition of
gastric H+,K+-ATPase.
Omeprazole was taken into clinical trials, and the first
publication on the efficacy in man was in 1983 (Gustavsson
et al., 1983). This and subsequent studies led to omeprazole
becoming available in Europe in 1988. Omeprazole is
recognized as a major breakthrough in the treatment of
GERD and PUD. Moreover, omeprazole is effective in the
treatment of Zollinger–Ellison syndrome (Lambers et al.,
1984), which was previously difficult to treat and often
required surgical intervention.
Other available PPIs include lansoprazole, pantoprazole,
rabeprazole, and esomeprazole, all of which are substituted
benzimadazoles. Tenatoprazole, which is in clinical devel-
opment, has an imidazopyridine ring instead of a benzima-
dazole ring but has the same mechanism of action as the
substituted benzimadazole PPIs. As illustrated by omepra-
zole, PPIs are more effective than H2RAs at reducing
intragastric pH and maintaining pH >4 for a longer period
of time (Bell et al., 1992). They are generally accepted to be
superior to H2RAs in the treatment of GERD and PUD, as
they relieve symptoms and heal lesions more effectively
than H2RAs (Chiba et al., 1997; van Pinxteren et al., 2001;
Salas et al., 2002). In addition, tolerance to PPIs has not
been documented (Tefera et al., 2001). The superior efficacy
of PPIs over H2RAs is attributed to the fact that they inhibit
gastric H+,K+-ATPase, independently of the nature of the
stimulus.
All PPIs are lipophilic compounds with weak base
properties and pKa values ranging from 3.8 to 5.0. Thus,
they easily penetrate cell membranes and are accumulated in
the highly acidic (pH ¨1.0) parietal cell canaliculi. For
example, omeprazole with a pKa of 4.0 would theoretically
concentrate 1000-fold in the parietal cell versus blood.
However, this equilibrium concentration will probably never
be achieved in vivo as the chemical stability of the
protonated form of omeprazole is extremely low. Within
milliseconds, the compound is degraded to form the active
inhibitor, the sulfenamide (Lindberg et al., 1987; Fig. 1).
Again, almost instantaneously, the sulfenamide binds
covalently to cysteine residues (in particular, cysteine 813
although other residues are involved) on the luminal side of
the a-subunit of the enzyme (Besancon et al., 1993, 1997).These cysteine residues do not appear to be necessary for
enzyme functioning, but their binding of the sulfenamide
may disrupt or prevent the conformational change of the
enzyme.
This mechanism of action results in the unique character-
istics of the pharmacokinetic–pharmacodynamic effect
pattern of PPIs. The inhibitory effect on acid secretion is
related to the amount of sulfenamide formed, which, for a
given dose, is related to the area under the plasma
concentration time curve (AUC). Thus, the maximal effect
of a given dose is correlated with the AUC rather than to the
Cmax, and there is no direct correlation between blood
plasma concentration and effect at any given time. The
duration of effect is determined by the half-life of the
sulfenamide–enzyme complex (at least 24 hr but may be as
long as 48 hr; Metz et al., 2002), rather than to the half-life
of the PPI in blood plasma (e.g., 1–2 hr for omeprazole).
Therapeutic oral doses of PPIs reach steady state and thus
achieve their maximal effect levels after 4–5 days of daily
dosing (Fig. 2). Therefore, PPIs in therapeutic doses have a
slow, cumulative onset of effect (e.g., 24–43% inhibition of
acid secretion on the first day of treatment and ¨80%
inhibition at steady state (Cederberg et al., 1992; Dammann
& Burkhardt, 1999).
After PPI administration, there is a return of acid
secretion that is partly due to de novo synthesis of the
enzyme (Im et al., 1985a; Gedda et al., 1995) and partly to
the dissolution of the enzyme–sulfenamide complex, owing
to the effect of endogenous glutathione (Im et al., 1985b;
Fujisaki et al., 1991). This dissociation may lead to the
reactivation of the enzyme, together with the release of a
sulfide corresponding to the PPI.
In addition to a cumulative onset of effect, PPIs have a
relatively slow onset of acute effect. PPIs are chemically
unstable at low pH, such as in the stomach (e.g., the half-
lives at pH 1.2 range from 1.3 to 4.7 min; Kromer et al.,
1998) and must be given in an acid-protected form, such as
enteric-coated granules. While such preparations allow PPIs
-
Fig. 2. Pharmacodynamic profile of a PPI demonstrating that there is a cumulative onset of effect at therapeutic oral doses.
K. Andersson, E. Carlsson / Pharmacology & Therapeutics 108 (2005) 294–307 299
to reach the intestine intact from where they can be
absorbed, they delay absorption.
Although PPIs have markedly advanced the treatment
of acid-related diseases, areas of medical need remain
(e.g., faster and more complete symptom relief, more
rapid healing). The degree and speed of onset of symptom
relief are important to patients (Kleinman et al., 2002).
However, not all patients with GERD experience complete
symptom relief after initial PPI therapy, which may
explain why many patients are unsatisfied with PPI
treatment (Crawley & Schmitt, 2000; Robinson & Shaw,
2002; Bytzer, 2003). Improved control of 24-hr intra-
gastric acidity would be likely to enhance symptom
resolution and healing, but as the limitations of PPIs
mainly relate to their shared mechanism of action, it is
likely that only incremental developments can be
achieved, making it attractive to consider other potential
approaches. The clinical utility of many of these strategies
(e.g., H3 receptor agonists, CCK2 receptor antagonists) is
likely to be limited, but 1 class of developmental agents
that holds promise for the treatment of acid-related
diseases is the P-CABs.
5. Potassium-competitive acid blockers
5.1. Development of the
potassium-competitive acid blocker class
During acid secretion, the surface of gastric
H+,K+-ATPase faces the extremely acidic parietal cell
canaliculus with a high affinity for K+. Given the
importance of the cation for enzyme function, agents that
compete with the binding of K+ have the potential to
block acid secretion. It is this principle that underlies the
mode of action of P-CABs (previously known as acid
pump antagonists or APAs). These agents can be classified
as imidazopyridines (e.g., SCH28080, AZD0865, and
BY841), pyrimidines (e.g., revaprazan), imidazonaphthyr-
idine (e.g., soraprazan), or quinolines (e.g., SK&F96067
and SK&F97574; Wallmark et al., 1987; Keeling et al.,
1991; Wurst & Hartmann, 1996; Tsukimi et al., 2000;
Park et al., 2003b; Briving et al., 2004).
The prototype P-CAB, SCH28080, was developed by
Schering-Plough (Ene et al., 1982; Long et al., 1983). In a
study published in 1982, this compound was shown to
inhibit gastric acid secretion in humans (Ene et al., 1982),
although its mechanism of action was not fully known at the
time. Subsequently, SCH28080 was shown to block gastric
H+,K+-ATPase by competing with K+ (Beil et al., 1986).
The development of SCH28080 ceased because of hepatic
toxicity. Despite this, the SCH28080 molecule has been
used extensively to investigate the functions of gastric
H+,K+-ATPase and provide insights into the mechanism of
action of the P-CAB class. Other compounds based on
SCH28080 were found to have improved bioavailability and
safety profiles (Kaminski et al., 1987, 1989; Scott et al.,
1987), including SCH33405. This compound was also
tested in humans (Sachs et al., 1995), but no publications
on these clinical studies are available.
Other P-CABs have provided further proof of principle
for this class of agents. SK&F96067 (BY067; Keeling et al.,
1988, 1991) was one of a series of quinolones that inhibited
gastric acid secretion and was investigated in early clinical
studies. It inhibited pentagastrin-simulated acid secretion
and was more effective than ranitidine in raising intragastric
pH (Pope & Parsons, 1993). SK&F97574 (BY574), an
analogue of SK&F96067 but with a longer duration of
action, inhibited H+,K+-ATPase in a potassium-competitive
fashion, blocked H+ transport in isolated gastric vesicles
(Pope et al., 1995), and inhibited histamine-stimulated
gastric acid secretion in the Heidenhain pouch dog (Parsons
et al., 1995). Preliminary toxicological studies did not reveal
any untoward findings (Leach et al., 1995), but although
taken into clinical studies (Pope & Parsons, 1993), the drug
is no longer under development. BY841 was found to be
more potent and more selective for the H+,K+-ATPase than
both SK&F96067 and SK&F97574 (Wurst & Hartmann,
1996). Based on positive preclinical and clinical Phase I
data (Wurst & Hartmann, 1996), BY841 entered Phase II
studies (e.g., comparing healing of reflux esophagitis
following BY841 and omeprazole treatment), but its
development was subsequently discontinued without pub-
lication of trial results.
Four representatives of the P-CAB class are currently in
clinical development to improve the treatment of acid-
-
Fig. 3. Mode of action of a P-CAB. As a P-CAB concentrates in the parietal
cell canaliculi, it is instantaneously protonated. It then binds ionically to the
gastric H+,K+-ATPase and inhibits acid secretion.
K. Andersson, E. Carlsson / Pharmacology & Therapeutics 108 (2005) 294–307300
related diseases (Table 1), with most information being
available on AZD0865 and revaprazan. Papers have been
published recently on other molecules (e.g., SPI447 [Ushiro
et al., 1997; Tsukimi et al., 2000], YJA20379-8 [Sohn et al.,
1999; Kim et al., 2000], and YJA20379-6 [Kim et al.,
1998]), but it is not clear if these agents are being evaluated
in humans.
5.2. Mechanism of potassium-competitive
acid blocker inhibition of gastric H+,K+-ATPase
P-CABs are lipophilic, weak bases that have high pKavalues and are stable at low pH. This combination of
properties allows them to concentrate in acidic environ-
ments. For example, the concentration of a P-CAB with a
pKa of 6.0 would theoretically be expected to be 100,000-
fold higher in the parietal cell canaliculus (pH 1) than in the
plasma (pH 7.4). The concentration of P-CABs in the gastric
mucosa is demonstrated by in vitro and in vivo studies with
AZD0865 and revaprazan (Park et al., 2003a; Briving et al.,
2004; Holstein et al., 2004c). In a radiolabeling study in rats,
the concentration of revaprazan reached peak levels in most
tissues at 4 hr after oral dosing. At 8 hr after oral dosing, the
radioactivity was highly localized in the gastric wall (Park et
al., 2003a). AZD0865 was tested in 2 different preparations
with isolated H+,K+-ATPase: in ion-tight and in ion-leaky
vesicles. In the ion-tight vesicle preparation, the high-
affinity K+-binding site faces intravesically and the vesicles
have an acidic internal environment. In the ion-leaky
vesicle, no acidic environment is formed. AZD0865 was
found to be more potent in ion-tight versus ion-leaky
vesicles, which suggests that it concentrates in regions of
low pH (Briving et al., 2004). Further evidence that
AZD0865 concentrates in acidic environments is provided
by studies in Heidenhain pouch dogs. For example, the
concentration of AZD0865 in gastric juice exceeded the
plasma concentration at ¨2 hr after dose (Holstein et al.,
2004b), and while the P-CAB was detectable in gastric juice
at 24 hr postdose, it was undetectable in plasma in most
animals (Holstein et al., 2004c).
On entering an acidic environment, P-CABs are instantly
protonated and it is in this form that it is thought to bind to
and inhibit the enzyme (Fig. 3). In keeping with this
hypothesis, the potency of P-CABs increases as pH falls
Table 1
P-CABS currently in clinical development
P-CAB Description Clinical
development
phase
Company
AZD0865 Imidazopyridine Phase II AstraZeneca
CS526 (R105266) Pyrrolopyridazine Phase I Sankyo and
Ube/Novartis
Revaprazan
(YH1885, Revanex)
Pyrimidine Phase III Yuhan
Soraprazan (BY359) Imidazonaphthyridine Phase II Altana
(Briving et al., 1988, 2004; Keeling et al., 1991; Pope et al.,
1995; Tsukimi et al., 2000). In ion-leaky vesicles, the IC50value for AZD0865 at pH 6.4 was ¨7 times lower
compared with the value at pH 7.4 (0.13 and 1.00 AM,respectively). This corresponds very well to the availability
of 6- to 7-fold more protonated drug at pH 6.4 (Briving et
al., 2004) The protonated form of a P-CAB inhibits the
H+,K+,-ATPase by binding ionically to it (Wallmark et al.,
1987; Keeling et al., 1991; Tsukimi et al., 2000; Park et al.,
2003b; Briving et al., 2004), as illustrated by the recovery of
enzyme activity after washout of AZD0865 and revaprazan
(Park et al., 2003a; Briving et al., 2004).
There appear to be separate binding sites on the gastric
H+,K+-ATPase for P-CABs and K+. For example, K+
affinity is not affected by mutations in the membrane
domains that reduce affinity for SCH28080 (and vice versa;
Asano et al., 1999; Lambrecht et al., 2000; Munson et al.,
2000; Vagin et al., 2001, 2002). Nevertheless, the K+-
competitive nature of P-CAB binding indicates that some of
the residues at or near the cation binding sites are involved
in P-CAB binding. Research indicates that P-CABs have a
luminal site of action (Wallmark et al., 1987; Keeling et al.,
1989; Pope & Parsons, 1993; Briving et al., 2004).
Investigations with SCH28080 indicate the likely binding
site of P-CABs. An early photoaffinity labeling study
suggested that the first extracellular loop (between M1
and M2) was the direct binding site of SCH28080 (Munson
et al., 1991), although subsequent mutational studies
indicate that this is not the case (Asano et al., 1997,
1999). Several areas of research (e.g., mutational studies,
NMR studies) indicate that the SCH28080 binding site is
located in the M1 to M6 and possibly M8 domains (Watts et
al., 2001; Vagin et al., 2002, 2003; Asano et al., 2004; Yan
et al., 2004). SCH28080 and SPI447 both bind in a cavity
formed by the M1, M4, M5, M6, and M8 transmembrane
segments, and by loops formed by M5/M6, M7/M8, and
M9/M10 (Asano et al., 2004). This cavity appears to be
separate from the cation-binding site.
P-CABs are believed to bind to gastric H+,K+-ATPase
when the enzyme is in its phosphorylated E2 form and/or
in its (nonphosphorylated) E2 form (Keeling et al., 1989;
Mendlein & Sachs, 1990). Support is provided by the
observed 10-fold increase in the binding affinity of
SCH28080 for the enzyme in the presence of ATP
-
K. Andersson, E. Carlsson / Pharmacology & Therapeutics 108 (2005) 294–307 301
(Wallmark et al., 1987; Keeling et al., 1989). Conceptually,
the binding of a P-CAB to the phosphorylated E2 form is
consistent with the fact that K+ binds to the same form of
the enzyme and that P-CABs compete with this ion. The
docking of a P-CAB in its binding site on the gastric
H+,K+-ATPase appears to stabilize the enzyme in the E2conformation (Asano et al., 2004) and prevents the
translocation of H+ ions. A P-CAB molecule may be
unable to bind to the E1 form of the enzyme due to re-
arrangement of transmembrane segments and loops that
form the P-CAB binding site. It appears that the
orientation of the loop between the M3 and M4 domains
in the E1 form of the enzyme prevents a P-CAB molecule
from occupying its binding site (Asano et al., 2004).
5.3. Selectivity of potassium-competitive
acid blockers for gastric H+,K+-ATPase
There are 3 main classes of enzymes that translocate
H+ in biological systems: P-type, F-type, and V-type of
H+-ATPases. V-type H+-ATPases are found in endomem-
branes and plasma membranes, and the F-type is located
in mitochondria. The P-type H+-ATPases are part of a
general class of ion-translocating ATPase that are charac-
terized by the formation of a covalently phosphorylated
enzyme intermediate as part of their catalytic cycle
(Rabon & Reuben, 1990). Members of this class include
gastric H+,K+-ATPase, Na+,K+-ATPase, and Ca+-ATPases
of sarcoplasmic reticulum and plasma membrane
(Sachs, 1994). The amino acid sequence of the human
H+,K+-ATPase is highly homologous (¨60%) to that of
the human Na+,K+-ATPase (Maeda et al., 1990). The
importance of K+ for physiological functioning dictates
that P-CABs must not affect other processes which
involve this cation, such as the ion exchange by
Na+,K+-ATPase. Data from studies of P-CABs no
longer in development show that they have a much
higher selectivity for gastric H+,K+-ATPase than for
Na+,K+-ATPase (Keeling et al., 1991; Kromer et al., 2000;
Tsukimi et al., 2000): SCH28080 has little effect on
Na+,K+-ATPase activity even at a concentration of 100
AM compared with an IC50 value of 1.3 AM for theinhibition of the H+,K+-ATPase (Beil et al., 1986);
SK&F96067 was 32-fold more selective for H+,K+-ATPase
than Na+,K+-ATPase; and SK&F97574 was 60-fold more
selective for H+,K+-ATPase than Na+,K+-ATPase (Pope et
al., 1995). The data available on compounds that are
currently in clinical development also demonstrate high
selectivity for gastric H+,K+-ATPase. AZD0865 is more
than 100-fold selective for gastric H+,K+-ATPase over
Na+,K+-ATPase. At a concentration of 100 AM, itreduced Na+,K+-ATPase activity by only 9% compared
with an IC50 value of 1.0 AM for the inhibition of theH+,K+-ATPase (Andersson et al., 2004). Revaprazan is
also more than 100-fold more selective for H+,K+-ATPase
over Na+,K+-ATPase (Park et al., 2003b).
H+,K+-ATPase isoforms found in rat and guinea pig
distal colon are not inhibited significantly by SCH28080
(Cougnon et al., 1996). In support of the targeting of
P-CABs for gastric H+,K+-ATPase in the parietal cell
canaliculus, AZD0865 does not appear to affect kidney
function despite the occurrence of the enzyme in the
cortical collecting duct of the kidney (Andersson et al., in
press). The weak base properties and, thus, the super-
concentration of P-CABs at areas of low pH probably
contribute significantly to the targeting, as P-CABs are
unlikely to concentrate to any great extent at sites with
relatively high pH.
P-CABs are also more selective for gastric H+,K+-ATPase
than for other H+-translocating ATPases, such as
vacuolar-ATPases, that are responsible for generating an
acidic pH in intracellular compartments. This selectivity
is illustrated by the selectivity of SK&F 96067 for
vacuolar-ATPase derived from avian osteoclasts and by the
insensitivity to SCH28080 in a similar preparation (Pope
& Sachs, 1992; Mattsson et al., 1993). As this type of
ATPase is highly conserved, it is unlikely that mammalian
vacuolar-ATPase will be inhibited by P-CABs.
5.4. Pharmacokinetics of
potassium-competitive acid blockers
After oral doses, P-CABs rapidly achieve peak plasma
concentrations in both animals and humans. This is partly
because the compounds are stable at low pH and so can be
administered as immediate-release formulations. A clinical
study of BY841 reported peak serum concentrations
between 0.5 and 1.5 hr after administration (Wurst &
Hartmann, 1996). In a volunteer study, the plasma concen-
tration of revaprazan reached peak levels within 1.3 to 2.5 hr
after a single dose (Yu et al., 2004). The Cmax of AZD0865
after oral administration to Heidenhain pouch dogs was
generally achieved 0.5–1 hr postdose (Andersson et al.,
2004). In humans, AZD0865 was rapidly absorbed and
maximum plasma concentrations occurred within 1 hr in
most subjects (Nilsson et al., 2005).
The P-CABs investigated to date exhibit linear pharma-
cokinetics. The Cmax and AUC of BY841 increased in
proportion with increasing dose (20–400 mg; Wurst &
Hartmann, 1996). The serum t1/2 of BY841 was unchanged
on repeated dosing, although a slight increase in AUC was
observed (Wurst & Hartmann, 1996). The oral bioavail-
ability of AZD0865 in Heidenhain pouch dogs was ¨50%
and the compound had linear pharmacokinetics over the
dose range 0.125–1 Amol/kg (Holstein et al., 2004b,2004d). Consistent with the findings from animal studies,
there was a proportional increase in AUC and Cmax with
dose in human subjects receiving single oral doses of
AZD0865 (0.08–4.0 mg/kg; Nilsson et al., 2005). The
plasma concentration–time profiles of AZD0865 are inde-
pendent of the number of doses given (Holstein et al.,
2004b, 2004d). For example, there was no increase in the
-
K. Andersson, E. Carlsson / Pharmacology & Therapeutics 108 (2005) 294–307302
plasma concentration of AZD0865 as a result of repeated
administration to chronic fistula rats or Heidenhain pouch
dogs (Holstein et al., 2004a, 2004c).
In rats and dogs, revaprazan had linear pharmacoki-
netics for oral doses of 2–30 mg/kg. In this dose range,
oral bioavailability was 41–47% in rats and 43–59% in
dogs (Park et al., 2003a). However, at doses above
200 mg/kg, the AUC of revaprazan did not show dose
proportionality, which was attributed to poor water
solubility of the drug (Han et al., 1998). On repeated
administration to rats and dogs, the daily pharmacokinetic
profiles of revaprazan were similar during 7 days of
dosing (Park et al., 2003a). A clinical study confirmed
that revaprazan has linear pharmacokinetic characteristics
and demonstrated little accumulation after multiple admin-
istrations (Yu et al., 2004).
The lipophilicity and chemical stability of the P-CAB,
together with the ionic binding between the agent and the
H+,K+-ATPase, facilitates an equilibrium between blood and
the secretory canaliculi, albeit with the concentration in the
latter being much higher.
5.5. Pharmacodynamics of
potassium-competitive acid blockers
The rapid absorption of P-CABs is mirrored by a fast
onset of acid inhibition. In animal and clinical studies,
there was a rapid inhibition of acid secretion with BY841
(Wurst & Hartmann, 1996; Kromer et al., 2000). A single
dose of BY841 quickly raised intragastric pH to ¨6 in
the pentagastrin-stimulated fistula dog and did so faster
than omeprazole (Wurst & Hartmann, 1996). In healthy
volunteers, a single 50 mg oral dose of BY841 increased
intragastric pH to about 6 within 30–60 min (Wurst &
Hartmann, 1996). For AZD0865, peak antisecretory effect
in the rat was achieved within 2 hr after an oral dose of
1 Amol/kg (Holstein et al., 2004d). The onset of effectwas also fast in dogs (e.g., peak antisecretory effect was
achieved within 3 hr postdose; Holstein et al., 2004d). In
humans, high doses of AZD0865 resulted in over 95%
inhibition of acid secretion within 1 hr after oral dosing
(Nilsson et al., 2005). In humans, revaprazan at single
doses of 150 mg and above rapidly increased mean
intragastric pH (Yu et al., 2004).
Fig. 4. Theoretical pharmacodynamic profile of a P-CAB demonstrating that these
of acid inhibition with subsequent, repeated doses.
The peak levels of acid secretion inhibition with
AZD0865 did not change over 5- and 14-day dosing
periods in Heidenhain pouch dogs and full effect was
achieved with the first dose (Andersson et al., 2004; Hol-
stein et al., 2004b). Similarly, intragastric pH was similar at
days 1 and 7 in a clinical study of revaprazan (Park et al.,
2002; Fig. 4).
P-CABs exhibit a classical (sigmoid) dose–response
profile, with the magnitude and duration of effect being
determined by dose, pKa, and plasma half-life. BY841 had a
dose-dependent duration of action in animal studies
(Kromer et al., 2000). In chronic fistula rats, AZD0865
provided dose-dependent inhibition of acid secretion (ED50value for inhibition of acid output of 0.3 Amol/kg), withdoses above 10 Amol/kg almost completely inhibitinggastric acid production 24 hr after administration (Holstein
et al., 2004a). Dose-dependent effects were also seen in
Heidenhain pouch dogs (ED50=0.28 Amol/kg; Holstein etal., 2004b). Confirming the relationship between pharma-
cokinetics and effect, there was a close correlation between
maximum inhibition of acid output and the logarithm of
Cmax for AZD0865 (EC50=130 nmol/L; Andersson et al.,
2004). In humans, AZD0865 demonstrated a dose–effect
relationship with a dose-dependent duration of inhibition of
acid secretion; more than 95% inhibition was sustained for
up to 15 hr for 0.8 and 1 mg/kg doses (EC50=100 nmol/L;
Nilsson et al., 2005). Dose-related pharmacodynamics were
noted in 46 healthy volunteers after single doses of
revaprazan (Yu et al., 2004). In a multiple-dose, crossover
study in which patients received 100, 150, and 200 mg once
daily for 7 days, mean intragastric pH on day 7 was 1.9, 3.5,
and 4.2, respectively (Park et al., 2002).
5.6. Pharmacodynamic comparisons of
potassium-competitive acid blockers with other agents
To date, there have been only a limited number of
published studies comparing P-CABs and other inhibitors of
acid secretion. In the pentagastrin-stimulated fistula dog, a
single dose of BY841 raised intragastric pH more rapidly
than omeprazole or ranitidine and elevated it almost to
neutrality, whereas omeprazole and ranitidine produced only
a moderate increase in pH (Kromer et al., 2000). When
histamine was used as a stimulus in the Ghosh-Schild rat,
agents achieve their full effect with the first dose and provide similar levels
-
Fig. 5. Comparison of acid blockade by the P-CAB, BY841, and omeprazole, a PPI. Note acid inhibition occurring within 30 min and the higher pH with
BY841. Reproduced from Wurst and Hartmann (1996) with permission from Yale J Biol Med.
K. Andersson, E. Carlsson / Pharmacology & Therapeutics 108 (2005) 294–307 303
BY841 and ranitidine displayed similar efficacy (Kromer et
al., 2000). Revaprazan was 3 times more potent than
omeprazole at inhibiting basal acid secretion in pylorus-
ligated rats and chronic fistula rats (Park et al., 2003b), and
was also more potent than omeprazole in inhibiting
histamine-stimulated gastric acid secretion in Heidenhain
pouch dogs. However, there was no significant difference in
inhibitory potency between revaprazan and omeprazole on
pentagastrin-stimulated gastric acid secretion in the lumen-
perfused rat (Park et al., 2003b). Soraprazan was found to be
more effective than ranitidine in raising pH within the
mucous layer of the fistula dog (Kromer et al., 2000).
There is only 1 published study in humans that allows
direct comparison to be made between P-CABs and other
therapies, but it does indicate pharmacodynamic differences
between the compounds. BY841 100 mg twice daily
markedly elevated intragastric pH and prolonged the
percentage of time at which pH was �4 on the first day ofdosing (Wurst & Hartmann, 1996; Fig. 5). In contrast,
omeprazole 20 mg once daily had only minor effects. After 7
days of dosing, BY841 was judged to be at least comparable
to omeprazole. The authors of the study expected the
differences between the agents to translate into a shortening
of healing time and a more rapid relief of symptoms. Taken
together, this clinical study and the animal studies indicate
that P-CABs offer more rapid and more profound elevation
of pH than a PPI or an H2RA, although the relative effects
appear to differ according to the model employed.
6. Summary
The evolution of our understanding of the biochemistry
and physiology of gastric acid secretion has led to the
development of therapies to inhibit gastric acid secretion.
PPIs are currently recognized to be the most effective
available agents for the treatment of acid-related diseases.
They offer superior symptom control and healing rates
compared with H2RAs in both PUD and GERD. However,
PPIs exhibit a delayed onset of acute effect and achieve full
effect only slowly and incrementally over several dose cycles.
A number of alternative therapeutic strategies have been
pursued with the objective of further improving the manage-
ment of acid-related diseases. Of these, the agents that have
progressed the furthest are CCK2 receptor antagonists and
P-CABs, with representatives of both classes in clinical trials.
CCK2 receptor antagonists are unlikely to become
alternative therapies to H2RAs or PPIs, especially given the
phenomenon of tolerance observed with an example of the
class. Thus, P-CABs appear to offer the most promise of the
newer agents, with initial studies comparing P-CABs with
PPIs suggesting pharmacodynamic differences between the 2
classes. P-CABs rapidly achieve therapeutic plasma levels
and concentrate in the acidic environment of the parietal cell
canaliculus. Once there, these compounds block gastric
H+,K+-ATPase by a K+ competitive binding at or near the
K+ binding site. They achieve their full effect quickly and
provide similar acid inhibition with the first dose and
subsequent, repeated doses. The results of comparative
clinical studies with PPIs will help to define the place of P-
CABs in the management of acid-related diseases.
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Potassium-competitive acid blockade: A new therapeutic strategy in acid-related diseasesIntroductionPhysiology of acid secretionStructure and properties of gastric H+,K+-ATPaseTargeting gastric acid secretionH2 receptor antagonists and H3 receptor agonistsMuscarinics and cholecystokinin2 receptor antagonistsProton pump inhibitors
Potassium-competitive acid blockersDevelopment of the potassium-competitive acid blocker classMechanism of potassium-competitive acid blocker inhibition of gastric H+,K+-ATPaseSelectivity of potassium-competitive acid blockers for gastric H+,K+-ATPasePharmacokinetics of potassium-competitive acid blockersPharmacodynamics of potassium-competitive acid blockersPharmacodynamic comparisons of potassium-competitive acid blockers with other agents
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