Drug Evaluation
`
`Drugs 32: 15-47 (1986)
`0012-6667/86/0007-0015/$16.50/0
`© ADIS Press Limited
`All rights reserved.
`
`Omeprazole
`A Preliminary Review of its Pharmacodynamic and
`Pharmacokinetic Properties, and Therapeutic Potential in
`Peptic Ulcer Disease and Zollinger-Ellison Syndrome
`
`Stephen P. Clissold and Deborah M. Campoli-Richards
`ADIS Drug Information Services, Auckland
`
`Various sections of the manuscript reviewed by: W. BeU, Abteilung Allgemeine Phar(cid:173)
`makologie, Medizinische Hochschule Hannover, Hannover, W. Germany; T. Berglindh,
`Center for Ulcer Research and Education, UCLA School of Medicine, Los Angeles, Cal(cid:173)
`ifornia, USA; J.D. Gardner, Department of Health & Human Services, National Institute
`of Health, Bethesda, Maryland, USA; C. W. Howden, Department of Materia Medica,
`Stobhill General Hospital, Glasgow, Scotland; M .J.S. Langman, Department of Thera(cid:173)
`peutics, University Hospital, Nottingham, England; W. Londong, Medizinische Klinik
`Innenstadt, University of Munich, Munich, West Germany; D.W. Piper, Royal North
`Shore Hospital, St Leonards, New South Wales, Australia; R.E. Pounder, Academic De(cid:173)
`partment of Medicine, The Royal Free Hospital, London, England; G. Sachs, Center for
`Ulcer Research and Education, UCLA School of Medicine, Los Angeles, California, USA;
`K.-Fr. Sewing, Abteilung Allgemeine Pharmakologie, Medizinische Hochschule Han(cid:173)
`nover, Hannover, W. Germany; B. Simon, Gastroenterologische Abteilung, Medizinische
`Universitatsklinik, Heidelberg, W. Germany; A. Waliln, Department of Internal Medi(cid:173)
`cine, University Hospital, Link6ping, Sweden; R.P. Walt, Department of Therapeutics,
`University Hospital, Nottingham, England; K.G. Wormsley, Ninewells Hospital, Ninew(cid:173)
`ells, Dundee, Scotland; N.D. Yeomans, Department of Medicine, Austin Hospital, Hei(cid:173)
`delberg, Victoria, Australia.
`
`Contents
`
`Summary ....................................................................................................................................... 16
`I. Pharmacodynamic Studies ...................................................................................................... 19
`1.1 Site and Mechanism of Action of Omeprazole .............................................................. 19
`1.1 .1 Site of Action ........................................................................................................... 20
`1.1.2 Mechanism of Action .............................................................................................. 21
`1.2 Effects on Gastric Acid Secretion .................................................................................... 23
`1.2.1 Animal Studies ......................................................................................................... 23
`1.2.2 Studies in Healthy Volunteers ................................................................................ 23
`1.2.3 Studies in Patients with Duodenal Ulcer Disease ................................................ 25
`1.2.4 Studies in Patients with Zollinger-Ellison Syndrome ........................................... 26
`1.3 Effects on Other Gastric Juice Constituents .................................................................. 26
`1.3.1 Pepsin ........................................................................................................................ 26
`1.3.2 Intrinsic Factor ......................................................................................................... 27
`1.4 Effects on Gastrointestinal Hormones ............................................................................ 27
`1.4.1 Serum Gastrin .......................................................................................................... 27
`
`DRL EXHIBIT 1023 PAGE 1
`
`

`

`Omeprazole: A Preliminary Review
`
`16
`
`Summary
`
`1.4.2 Other Gastrointestinal Hormones .......................................................................... 28
`1.5 Effects on Gastric Emptying Rate ................................................................................... 28
`1.6 Effects on Endocrine Function ........................................................................................ 28
`1.7 Prevention of Experimental Gastric Mucosal Damage ................................................. 28
`1.8 Effects on Gastric Mucosal Morphology ........................................................................ 29
`1.9 Effects on Intragastric Bacterial Activity and Nitrosamine Concentrations ................ 31
`2. Pharmacokinetic Studies ......................................................................................................... 31
`2.1 Absorption, Plasma Concentrations, and Bioavailability .............................................. 31
`2.2 Distribution ....................................................................................................................... 33
`2.3 Metabolism and Excretion ............................................................................................... 34
`2.3.1 Elimination Half-Life ............................................................................................... 34
`2.4 Studies in Patients with Duodenal Ulcer Disease or Zollinger-Ellison Syndrome ..... 35
`2.5 Studies in Patients with Chronic Renal Disease ............................................................ 35
`2.6 Relationship Between Plasma Concentration and Antisecretory Activity ................... 35
`3. Therapeutic Trials ................................................................................................................... 35
`3.1 Treatment of Duodenal Ulcers ........................................................................................ 36
`3.1.1 Dose-Ranging Studies .............................................................................................. 36
`3.1.2 Open Studies ............................................................................................................ 36
`3.1.3 Omeprazole Compared with Cimetidine or Ranitidine ....................................... 37
`3.2 Treatment of Ulcerative Peptic Oesophagitis ................................................................. 38
`3.3 Treatment of Gastric Ulcers ............................................................................................ 39
`3.4 Treatment of Zollinger-Ellison Syndrome ...................................................................... 39
`4. Side Effects and Effects on Laboratory Variables ................................................................ 40
`5. Drug Interactions ..................................................................................................................... 41
`6. Dosage and Administration ................................................................................................... .42
`7. Place of Omeprazole in Therapy .......................................................................................... .42
`
`Synopsis: Omeprazolel is a substituted benzimidazole derivative which markedly in(cid:173)
`hibits basal and stimulated gastric acid secretion. It has a unique mode of action. irre(cid:173)
`versibly blocking the so-called proton pump of the parietal cell which is supposedly the
`terminal step in the acid secretory pathway.
`In animals. on a weight basis. omeprazole is 2 to 10 times more potent than cimetidine
`in inhibiting gastric acid secretion. Toxicological studies in rats have shown that very high
`doses of omeprazole administered for 2 years produce hyperplasia of gastric enterochro(cid:173)
`maffin-like cells and carcinoids, a few with proliferations into the submucosa. The sig(cid:173)
`nificance of such findings to the clinical situation is wholly speculative and requires further
`research. Preliminary studies in patients with duodenal ulcers or Zollinger-Ellison syn(cid:173)
`drome have found no mucosal changes which would suggest that the drug represents a
`risk for development of carcinoid tumours at therapeutic dosages.
`In patients with duodenal ulcers omeprazole. at dosages of at least 20mg once daily.
`produced ulcer healing rates of between 60 and 100% after 2 weeks and between 90 and
`100% after 4 weeks. even in patients resistant to treatment with Hrreceptor antagonists.
`Comparative trials clearly demonstrated that omeprazole 20 to 40mg administered once
`daily was significantly more effective than usual dosage regimens of cimetidine and ran(cid:173)
`itidine in healing duodenal ulcers during 2 to 4 weeks of treatment. At present no data
`are available evaluating omeprazole as maintenance therapy once ulcers have healed.
`Other clinical trials have also shown that omeprazole is effective for treating gastric ulcers.
`ulcerative peptic oesophagitis. and Zollinger-Ellison syndrome. In patients with Zollinger(cid:173)
`Ellison syndrome the profound and long lasting antisecretory activity of omeprazole may
`make it the drug of choice for treating the massive acid hypersecretion associated with
`the disease. especially when H2-receptor antagonists are ineffective. During clinical trials
`
`I
`
`'Losee', 'Lozec', 'Losek' (AB Hassle, Astra; not yet commercially available).
`
`DRL EXHIBIT 1023 PAGE 2
`
`

`

`Omeprazole: A Preliminary Review
`
`17
`
`reported to date omeprazole has been very well tolerated but further clinical experience is
`essential to fully evaluate its safety profile.
`Thus. omeprazolerepresents a pharmacologically unique antisecretory drug which is
`very effective for rapidly healing peptic ulcers and peptic oesophagitis. and for reducing
`gastric acid hypersecretion in patients with Zollinger-Ellison syndrome. If the apparent
`absence of undesirable mucosal morphological changes during treatment with usual doses
`in patients with peptic ulcer disease is confirmed. it may be a major advance in the treat(cid:173)
`ment of these diseases.
`
`Pharmacodynamic Studies: In vitro and in vivo animal studies demonstrated that ome(cid:173)
`prazole produces long lasting inhibition of gastric acid secretion which is likely due to
`non-competitive binding ofa proton-activated derivative to parietal cell (H+fK+)-ATPase.
`Such a mechanism, at the terminal stage of the acid secreting process, means a reduction
`of intragastric acidity can now be achieved independent of the nature of the primary
`stimulus. Comparative studies in animals found omeprazole to be some 2 to 10 times
`more potent than cimetidine on a weight basis.
`Single-dose studies in man (healthy volunteers and patients with duodenal ulcer dis(cid:173)
`ease or Zollinger-Ellison syndrome) have shown that omeprazole inhibits both basal and
`stimulated gastric acid secretion in a dose-dependent manner. Following repeat once daily
`administration, omeprazole has an increasing effect on acid secretion which appears to
`stabilise after about 3 days. Short term studies indicate that 20 to 30mg once daily is the
`optimum dosage regimen in healthy volunteers and patients with duodenal ulcer disease
`in remission; this virtually abolishes gastric acidity within 6 hours and reduces stimulated
`acid output after 24 hours by 60 to 70%.
`In addition to its effects on gastric acidity, omeprazole reduces the total volume of
`gastric juice secreted and inhibits pepsin output. However, these changes are not as con(cid:173)
`sistent or as great as the effect on acid secretion. Omeprazole 0.35 mg/kg administered
`intravenously did not significantly affect basal or stimulated intrinsic factor secretion.
`Furthermore, omeprazole does not seem to have any significant influence on gastric
`emptying rate, or on the majority of gastrointestinal hormones - apart from gastrin. Short
`periods of treatment with omeprazole administered once daily usually resulted in ele(cid:173)
`vated serum gastrin levels. Such hypergastrinaemia occurs secondary to a pronounced
`reduction of intragastric acidity, and returns to normal levels within I to 2 weeks of
`. stopping treatment.
`Orally, but not parenterally, administered omeprazole seems to be cytoprotective in
`some animal models of peptic ulcer disease such as Shay ulcers, stress-induced ulcers,
`and ulcers induced by various necrotising agents. The mechanisms involved are not fully
`understood but appear to be independent of the established anti secretory properties of
`omeprazole.
`Toxicological studies in rats have demonstrated that supramaximal doses of orne(cid:173)
`prazole administered for long periods cause gastric enterochromaffin-Iike cell hyperplasia
`and carcinoids, a few with proliferations into the submucosa. It has been suggested that
`hypergastrinaemia, induced by the profound inhibition of gastric secretion causes these
`changes; their relevance to the therapeutic use of omeprazole remains speculative and
`further studies are required.
`
`Pharmacokinetic Studies: The absorption characteristics of omeprazole are both form(cid:173)
`ulation- and dose-dependent. Following administration of the drug as a buffered oral
`solution, buffered encapsulated uncoated granUles, or as capsules of enteric-coated gran(cid:173)
`ules, mean peak plasma omeprazole concentrations were attained after 20 minutes, 30
`minutes, and between 2 and 5 hours, respectively. Interestingly, increased doses of ome(cid:173)
`prazole produced disproportionately larger increases in mean peak plasma concentration
`and systemic availability. Similarly, repeat once daily administration for 5 to 7 days
`resulted in significant elevations of mean peak plasma concentration and area under the
`plasma concentration-time curve. Since omeprazole is acid labile, these findings could
`
`DRL EXHIBIT 1023 PAGE 3
`
`

`

`Omeprazole: A Preliminary Review
`
`18
`
`possibly indicate that the antisecretagogue improves its own absorption and relative bio(cid:173)
`availability by inhibiting acid secretion. An alternative explanation involves saturation
`of enzymes responsible for the first-pass metabolism of omeprazole.
`Following intravenous administration omeprazole plasma concentrations decline
`biexponentially. The apparent volume of distribution of omeprazole is about 0.3 to 0.4
`L/kg which is compatible with localisation of the drug in extracellular water. Penetration
`of omeprazole into red blood cells is low, whereas its plasma protein binding is high -
`between 95 and 96% in human plasma.
`Omeprazole is eliminated rapidly and almost completely by metabolism; no un(cid:173)
`changed drug has been recovered in the urine. Following absorption, 3 metabolites of
`omeprazole have been identified: a sulphone derivative, a sulphide derivative and hy(cid:173)
`droxyomeprazole. Peak plasma concentrations of the sulphone metabolite are attained
`shortly after those of unchanged omeprazole, 0.4 to 1.7 hours after peak omeprazole
`concentrations following administration of capsules of enteric-coated granules. However,
`unidentified metabolites of omeprazole had a very similar plasma concentration-time
`curve as the parent drug - in terms of peak concentration and the time to achieve it.
`Following administration of 14C-omeprazole approximately 60% of total radioactivity is
`recovered in the urine within 6 hours. Over a ~y period about 80% of the administered
`dose was recovered in the urine and the remainder in the faeces. Total plasma clearance
`is relatively high (32 to 40 L/h) and most studies have reported a mean elimination half(cid:173)
`life of omeprazole in healthy subjects of between 0.5 and 1.5 hours (usually about I
`hour).
`There are limited data available concerning the pharmacokinetic properties of ome(cid:173)
`prazole in patients with peptic ulcer disease or Zollinger-Ellison syndrome.
`The pharmacokinetic profile of omeprazole does not seem to be altered in patients
`with chronic renal failure and is not influenced by haemodialysis.
`Omeprazole plasma concentration does not correlate with its antisecretory activity at
`a given time-point; indeed, the drug markedly inhibits acid secretion long after plasma
`concentrations have decreased below detection limits. However, there does seem to be
`a significant correlation between antisecretory activity and area under the plasma con(cid:173)
`centration-time curve.
`
`Therapeutic Trials: Clinical trials have demonstrated that omeprazole at dosages of
`at least 20mg once daily produces a duodenal ulcer healing rate of between 60 and 100%
`within 2 weeks and between 90 and 100% within 4 weeks. Dose-finding studies showed
`that an optimal dosage of omeprazole is between 20 and 40mg once daily. Open clinical
`studies have confirmed these very high rates of duodenal ulcer healing even in a small
`group of patients who were refractory to treatment with H2-receptor antagonists (alone
`or in combination with other antiulcer drug!;). Appropriately designed comparative clinical
`trials clearly demonstrated that once-daily administration of omeprazole 20 to 40mg pro(cid:173)
`duces significantly more rapid healing of duodenal ulcers after 2 to 4 weeks of treatment
`than the H2-receptor antagonists cimetidine and ranitidine. Additionally, omeprazole 20mg
`and 40mg once daily elicited significantly greater symptom relief than ranitidine 150mg
`twice daily, whereas in 2 other studies 30mg and 20mg of omeprazole were indistin(cid:173)
`guishable from cimetidine 1000 mgfday and ranitidine 300 mgfday, respectively, in this
`respect. Other clinical studies have shown that omeprazole administered once daily may
`be effective for treating gastric ulcers and ulcerative peptic oesophagitis. Indeed, ome(cid:173)
`prazole 40mg once daily was significantly superior to ranitidine 150mg twice daily in
`178 patients with reflux oesophagitis. Furthermore, in a double-blind multicentre trial
`in 184 outpatients with gastric ulceration, omeprazole 20mg once daily was as effective
`as ranitidine l50mg twice daily and healed 95% of gastric ulcers within 8 weeks.
`In patients with Zollinger-Ellison syndrome, omeprazole is a highly potent and long
`acting antisecretagogue which many authors consider will become the drug of choice for
`controlling the massive acid hypersecretion associated with the disease. For patients with
`Zollinger-Ellison syndrome who are resistant to H2-receptor antagonists, omeprazole of-
`
`DRL EXHIBIT 1023 PAGE 4
`
`

`

`Omeprazole: A Preliminary Review
`
`19
`
`fers a valuable therapeutic alternative to surgery (partial or total gastrectomy) with its
`inherent risks.
`
`Side Effects: Preliminary experience with omeprazole has found the antisecretagogue
`to be well-tolerated, producing no consistent side effects or changes in laboratory vari(cid:173)
`ables. Wider clinical usage with careful surveillance is needed to fully evaluate the side
`effect profile of omeprazole.
`
`Dosage and Administration: The usual oral adult dosage of omeprazole seems to be
`20mg once daily before breakfast for 2 to 4 weeks for duodenal ulcers and 4 to 8 weeks
`for gastric ulcers. In patients with Zollinger-Ellison syndrome omeprazole dosage should
`be individualised so that the smallest dose is administered which reduces gastric acid
`secretion to less than 10 mEq for the last hour before the next dose. At present, insuf(cid:173)
`ficient data are available for dosage recommendations in children.
`
`1. Pharmacodynamic Studies
`
`Omeprazole (fig. 1) is a substituted benzimi(cid:173)
`dazole which markedly inhibits basal and stimu(cid:173)
`lated gastric acid secretion in animals and man. It
`is the first of a new class of antiulcer drugs likely
`to be introduced into clinical practice (it is not yet
`commercially available) and is thought to reduce
`acid secretion by inhibiting hydrogen/potassium
`adenosine triphosphatase [(H+/K+)-ATPase), be(cid:173)
`lieved to be the proton pump of the parietal cell.
`This mechanism, at the terminal stage of the acid
`secreting process, means that for the first time in(cid:173)
`tragastric acidity can be reduced independent of the
`nature of the primary stimulus. Since inhibition of
`gastric acid is a most important indicator of the
`therapeutic potential of drugs used to treat peptic
`
`Fig. 1. Structural formula of omeprazole.
`
`ulceration, oIl!eprazole might be expected to offer
`some advantages for the treatment of this disease.
`Independent of its clinical future, omeprazole is al(cid:173)
`ready an important pharmacological 'tool' for in(cid:173)
`vestigating physiological and biochemical changes
`that occur in the gastric mucosa and for evaluating
`the mechanisms of action of gastric acid inhibitors.
`
`1.1 Site and Mechanism of Action of
`Omeprazo1e
`
`Superficially, upper gastrointestinal ulceration
`has a relatively simple underlying aetiology which
`involves some loss of ability of the mucosa to pro(cid:173)
`tect against gastric acid and/or excessive secretion
`of acid. The complex morphological changes that
`occur with regard to mucosal cytoprotection in re(cid:173)
`lation to the various conditions found in the upper
`gut are currently poorly understood and drug treat(cid:173)
`ment has been largely devoted to controlling lu(cid:173)
`minal acidity (Berglindh & Sachs 1985).
`Hydrochloric acid, one major cause of upper
`gastrointestinal tract ulcers, is secreted from par(cid:173)
`ietal (oxyntic) cells by the gastric proton pump
`[gastric (H~/K+)-ATPase], distal to cyclic adeno(cid:173)
`sine monophosphate (cAMP), in response to at least
`3 different types of stimulation - cholinergic (va(cid:173)
`gal), histaminergic and gastrinergic (Sachs 1984)
`[fig. 2]. It follows that an individual antagonist to
`anyone of the 3 (or more) receptor types will only
`
`DRLEXHIBIT 1023 PAGE 5
`
`

`

`Omeprazole: A Preliminary Review
`
`20
`
`AntimuSC8rinic drugs
`
`Gastric (H+/K+)-ATPase
`inhibitors
`(e.g. omeprazole)
`
`/
`
`/
`
`/
`tI
`
`______ .H+
`
`--1t--------t. K+
`---i"~-----... CI-
`
`(e.g. Pirenzepine), ,
`,..----....,1'·
`t
`---- /~
`
`Acetylcholine
`
`_
`
`Gastrin
`
`)
`
`/
`
`1/
`Histamine> / 1f
`~
`
`/
`
`/
`Histamine H:rreceptor antagonists
`(e.g. clmetidlne and ranltidine)
`
`---Serosa--..... I ... ---Parietal cell---.~ I+--MUCOse--
`
`Fig. 2. A simple conceptual model of the parietal cell and some speculated mechanisms involved in the control and inhibition of
`gastric acid secretion (after Fiasse et al. 1984; Fimmel & Blum 1984; Lewin 1984; Rabon et ai. 1983).- -"'represents proposed
`mechanisms by which certain classes of antiulcer drugs antagonise gastric acid stimulation.- .... indicates other additional effects
`of the H2-receptor antagonists (although it is not necessarily at the receptor level) which may contribute to their antisecretory activity
`(for a review see Bowman & Rand 1980).
`
`partially block gastric acid secretion although there
`is evidence that the histamine-stimulated system
`may be dominant since histamine Hz-receptor ant(cid:173)
`agonists (cimetidine and ranitidine) seem capable
`of inhibiting a major portion of gastric acid secre(cid:173)
`tion. However, inhibition of the gastric proton
`pump, probably the terminal stage of the acid se(cid:173)
`creting pathway from the parietal cell, provides a
`means of blocking gastric acid secretion by a greater
`amount. This is the proposed site and mechanism
`of action of omeprazole (Berglindh & Sachs
`1985; Helander et al. 1985; Larsson et al. 1985b)
`[fig. 2].
`
`1.1.1 Site of Action
`Parietal cells are buried deep within the gastric
`mucosa (slightly beneath peptic cells). Their secre(cid:173)
`tory surfaces are covered with microvilli and are
`deeply invaginated to form channels termed can(cid:173)
`aliculi. The gastric proton pump [(H+/K+)(cid:173)
`ATPase], which has been discovered in frog (Gan(cid:173)
`ser & Forte 1973), hog (Saccomani et al. 1975) and
`human (Saccomani et al. 1979) gastric mucosa, has
`been isolated mostly from parietal cells although
`there is some evidence that it may be present in
`jejunal (White 1985) and colonic (Gustin & Good(cid:173)
`man 1981) mucosa. In gastric mucosa the proton
`
`DRL EXHIBIT 1023 PAGE 6
`
`

`

`Omeprazole: A Preliminary Review
`
`21
`
`pump is situated in the apical membrane and tub(cid:173)
`ulovesicles bordering the secretory canaliculi of the
`parietal cell (for reviews see Berglindh & Sachs
`1985; Olbe et al. 1979). Consequently, each can(cid:173)
`aliculus can be viewed as an invaginated extracel(cid:173)
`lular compartment of low pH (about pH 1). Such
`an environment should readily accumulate weak
`bases with a pKa higher than the pH of the gastric
`compartment (Berglindh & Sachs 1985; Sachs
`1984).
`Omeprazole is a substituted benzimidazole and
`a weak base (pKa = 3.97), which fulfills the criteria
`for accumulation within the acid space (Briind(cid:173)
`strom et al. 1985). Animal studies have provided
`strong evidence that the main site of action of
`omeprazole is indeed in the distal (to cAMP) por(cid:173)
`tion of the parietal cell. Thus, radiolabelled ome(cid:173)
`prazole administered intravenously to mice was
`shown to accumulate rapidly in gastric mucosa,
`liver, kidney, and in the choroid plexus, but after
`16 hours high levels of radioactivity remained only
`in the gastric mucosa. Autoradiography revealed
`that it was localised in the parietal cells and sub(cid:173)
`sequent electron microscopic autoradiography
`demonstrated that the radioactive label was almost
`exclusively found at the secretory surfaces and their
`immediate vicinity, and in regions of cytoplasm
`containing the tubulovesicles (Helander et al. 1983,
`1985).
`Fryklund et al. (1984) using separated and en(cid:173)
`riched parietal and chief cell fractions from rabbit
`gastric mucosa showed that omeprazole had a spe(cid:173)
`cific inhibitory effect on acid secretion from par(cid:173)
`ietal cells and did not influence stimulated release
`of pepsinogen from chief cells. However, DeflZe et
`al. (1985) found that omeprazole 0.1 mmol/L
`strongly stimulated secretion of preformed and re(cid:173)
`cently synthesised pepsinogen in isolated rabbit
`gastric glands even though it decreased pepsinogen
`synthesis. Similarly, Fimmel et al. (1984) observed
`that omeprazole 0.1 mmol/L stimulated pepsin re(cid:173)
`lease in the in vitro perfused mouse stomach model;
`the mechanism remains uncertain although the in(cid:173)
`crease does not seem to be due to a nonspecific
`leakage through disruption of chief cell membranes
`(Defize et al. 1985).
`
`The above findings and those from additional
`in vitro experiments (see section 1.1.2) clearly in(cid:173)
`dicate that the main site of action of omeprazole
`is in the parietal cell at a point distal to cAMP. It
`seems likely that the drug binds with (H+/K+)(cid:173)
`ATPase in the cytoplasm/tubulovesicles and secre(cid:173)
`tory surfaces bordering the canaliculi. However,
`Keeling et al. (1985) and Beil and Hackbarth (1985)
`demonstrated that omeprazole also inhibits (Na+ /
`K+)-ATPase isolated from dog kidneys, but to a
`lesser extent than its effects on (H+/K+)-ATPase.
`The authors noted that the acidic compartments of
`the parietal cell would impart a high degree of se(cid:173)
`lectivity onto omeprazole. Further evidence for the
`specificity of action of omeprazole is provided by
`Howden and Reid (1984) who reported that the
`drug had no demonstrable effects on renal electro(cid:173)
`lyte or renal acid excretion in healthy volunteers.
`
`1.1.2 Mechanism of Action
`Various in vitro preparations ranging from iso(cid:173)
`lated gastric mucosa to purified (H+fK+)-ATPase
`from parietal cells have been utilised to help define
`the mechanism of action of omeprazole (Wallmark
`et al. 1983, 1985). As can be seen in table I, ome(cid:173)
`prazole inhibits both basal and stimulated acid se(cid:173)
`cretion (irrespective of whether acid formation was
`stimulated by histamine, cAMP, high K+ levels, or
`exogenously added ATP). In contrast, cimetidine
`only antagonised histamine-stimulated gastric acid
`secretion which is consistent with its Hrreceptor
`blocking properties. Omeprazole and thiocyanate
`shared many common pharmacodynamic actions,
`although only omeprazole directly inhibited iso(cid:173)
`lated (H+/K+)-ATPase and Withstood attempted
`reversal by antipyrine of its acid inhibitory prop(cid:173)
`erties in isolated gastric mucosa. These findings
`highlight the late stage in the acid secreting process
`at which omeprazole exerts its inhibitory effects.
`The potency of omeprazole is markedly en(cid:173)
`hanced in an acidic environment (Beil & Hack(cid:173)
`barth 1985; Beil & Sewing 1985; Beil et al. 1985;
`1m et al. 1985b,c; Keeling et al. 1985; Wallmark et
`al. 1983, 1984, 1985, 1986). This CQuld be due to
`a change in parietal cell (H+/K+)-ATPase making
`it more susceptible to the effects of omeprazole at
`
`DRL EXHIBIT 1023 PAGE 7
`
`

`

`Omeprazole: A Preliminary Review
`
`22
`
`Table I. Summary of in vitro studies designed to elucidate the mechanism of action of omeprazole, compared with cimetidine and
`thiocyanate as reference drugs, with regard to inhibition of gastric acid secretion (after Beil & Sewing 1984; Larsson & Ryberg 1983;
`Larsson et a!. 1984; Sewing et a!. 1983; Wallmark et a!. 1983, 1985)
`
`Preparation
`
`Guinea-pig isolated gastric mucosa
`
`Rabbit isolated intact gastric glands
`
`Gastric acid
`stimulant
`
`Basal
`Histamine
`Dibutyryl-cAMP
`
`Basal
`Histamine
`Dibutyryl-cAMP
`K+
`
`Rabbit isolated permeable gastric glands ATP, K+
`
`Rabbit isolated parietal cells
`
`Histamine
`Dibutyryl-cAMP
`
`Pig isolated gastric (W/K+)-ATPase
`
`ATP, K+
`
`Guinea-pig (W/K+)-ATPase purified from
`parietal cells
`
`K+
`
`Guinea-pig isolated and enriched parietal Histamine
`cells
`Dibutyryl-cAMP
`
`Inhibitor of gastric acid secretion
`
`omeprazole
`
`cimetidine
`
`thiocyanate
`
`+
`+
`
`+
`+
`+
`+
`+
`
`+
`
`+
`
`+
`
`+
`+
`+
`+
`+
`+
`+
`+
`+
`+
`+
`+
`
`+
`+
`
`Abbreviations: cAMP = cyclic adenosine monophosphate; ATP = adenosine triphosphate; + = drug produced inhibition of gastric
`acid secretion; - = drug did not produce any inhibition of gastric acid secretion.
`
`low pH. However, at present, the weight of evi(cid:173)
`dence suggests that omeprazole is activated at acidic
`pH (probably by protonation) and that the H+-ac(cid:173)
`tivated derivative reacts with sulfhydryl groups as(cid:173)
`sociated with gastric (H+/K+)-ATPase (1m et al.
`I 985b,c; Keeling et al. 1985; Sewing & Hanne(cid:173)
`mann 1985; Wallmark et al. 1984). Beil and Sewing
`found
`that omeprazole could inhibit various
`sulfhydryl-containing A TPases but it was most ef(cid:173)
`fective against gastric (H+/K+)-ATPase. Thus, the
`unique low pH of the tubulovesicles should make
`the actions of omeprazole very specific since ome(cid:173)
`prazole preferentially accumulates at these low pH
`sites and an acid pH is necessary to activate the
`drug.
`A number of research groups have performed
`more detailed studies to determine the structure of
`the active form of omeprazole and the nature of
`its reaction with gastric (H+/K+)-ATPase (1m et al.
`
`1985c; Lorentzon et al. 1985; Rackur et al. 1985;
`Wallmark et al. 1986). Wallmark et al. (1986) re(cid:173)
`cently suggested that omeprazole acts in vivo, after
`being converted in the acid compartments of the
`parietal cell into a sulphenamide derivative, by
`forming a disulphide complex with the enzyme
`(H+/K+)-ATPase. Alternatively, a sulphenic acid
`form of omeprazole may react directly with the en(cid:173)
`zyme. These proposed mechanisms differ from
`those previously suggested by 1m et al. (1985c) and
`Rackur et al. (1985) and further studies are needed
`to elucidate the precise mechanisms involved in
`the inactivation of gastric (H+/K+)-ATPase.
`There is some conflict regarding the nature of
`the omeprazole/(H+/K+)-ATPase interaction. In
`vitro studies have shown that the inhibitory effects
`of omeprazole can be washed out (Berglindh et al.
`1985; Sewing et al. 1983, 1985) or they can be re(cid:173)
`versed by sulfhydryl-reducing compounds such as
`
`DRL EXHIBIT 1023 PAGE 8
`
`

`

`Omeprazo)e: A Preliminary Review
`
`23
`
`,B-mercaptoethanol. In vivo experiments demon(cid:173)
`strated that omeprazole produces long lasting in(cid:173)
`hibition of acid secretion which is likely due to ir(cid:173)
`reversible inhibition of parietal cell (H+/K+)(cid:173)
`ATPase (Berglindh et al. 1985; 1m et al. 1985a).
`The discrepancy between in vitro and in vivo re(cid:173)
`sults needs to be explained, although there is evi(cid:173)
`dence that omeprazole irreversibly inactivates (H+/
`K +)-A TPase in vivo and new enzyme has to be syn(cid:173)
`thesised before gastric acid secretory activity can
`be restored (1m et al. 1985a).
`
`binds with (H+/K+)-ATPase in the parietal cell. As
`a consequence of its long duration of action, re(cid:173)
`peated once daily administration of omeprazole re(cid:173)
`sulted in increased antise