`
`Dongs 32: 154'! (I986)
`00] ZMT/SfimeT-OOI SIS 16.50N
`O ADlS 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. Commit-Richards
`ADlS Drug Information Services. Auckland
`
`Various sections of the manuscript reviewed by: W. Bell, Abteilung Allgemeine Phar-
`makologie. Medizinisclle Hochschule Hannover, Hannover. W. Germany; T. Bastian},
`Center for Ulcer Research and Education, UCLA School of Medicine, Los Angeles, Cal-
`ifornia. USA; JED. Gardner; Department of Health & Human Services, National Institute
`of Health. Bethesda. Maryland. USA; CW. Handel. Department of Materia Medica,
`Stobhill General Hospital, Glasgow, Scotland; Mulls. Mme, Department of Thera-
`peutics. University Hospital, Nottingham, England; W. undoing, Medizinische Klinik
`Innenstadt, University of Munich. Munich, West Germany; DJV. Piper. Royal North
`Shore Hospital. St Leonards, New Scuth Wales. Australia; RE. Medan Academic De-
`partment of Medicine. The Royal Free Hospital. London, England; G. Sachs, Center for
`Ulcer Research and Education, UCLA School of Medicine, Dos Angeles, California, USA;
`K.-Fr. Sewing, Abteilung Allgemeine Pharmakologie, Medizinische Hochschule Han-
`nover, Hannover. W. Germany; E. Simon, Gastroenterologische Ahteilung, Medizinische
`Universitatsklinik. Heidelberg, W. Germany; A. Wotan. Department of Internal Medi-
`cine, University Hospital, Linkening, Sweden; R.P. Watt, Department of Therapeutics,
`University Hospital. Nottingham. England; KEG. Wormley, Ninewells Hospital. Ninew-
`ells, Dundee, Scotland; MD. Yeoman, Department of Medicine, Austin Hospital, Hei-
`delberg. Victoria, Australia.
`
`Contents
`
`
`
`Summary” 16
`I PharmacodynainicStudies............................................................ 19
`
`l. I Site and Mechanism of Action omeeprazole l9
`1.! 1 Site ofAction
`.......20
`I.I.2 Mechanism of Action
`.......2|
`I. 2 Effects on Gastric Acid Secretion
`...........23
`1.2.1 Animal Studies"
`....... 23
`1.2.2 Studies in Health;Volunteers
`..
`.......23
`
`1.23 StudiesIn Patients with Duodenal UlcerDisease .................25
`1.2.4 Studiesin Patients with Zollinger—Ellison Syndrome ........................................... 26
`1.3 Effects on Other Gastric Juice Constituents .................................................................. 26
`1.3.1 Pepsin ...........................................................
`...26
`
`...2'l
`1.3.2 Intrinsic Factor ................................
`
`.......................................... 2?
`1.4 Effects on Gastrointestinal Hormones
`1.4.] Serum Gastrin .......................................................................................................... 27
`
`
`
`Page 1
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`CFAD EXHIBIT 1052
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`Page 1
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`

`_ Omeprazole: A Preliminary Review
`
`o.
`1.4.2 Other Gastrointestinal Hormones
`'-
`1.5 Effects on Gastric Emptying Rate
`
`3.
`l.6 Effects on Endocrine Function ........................................................................................
`'
`1.? Prevention of Experimental Gastric Mucosal Damage
`
`1.8 Effects on Gastric Mucosa] Morphology ........
`
`1.9 Effects on Intragastric Bacteria] Activity and Nttrosamine Concentrations ..
`2. Pharmacokinetic Studies ......................................................................................................... 3‘
`2. I Absorption. Plasma Concentrations, and Bioavnilability ..............................................3
`22 Distribution
`...3.
`
`2.3 Metabolism and Excretion ..
`'
`2.3.1 Elimination Half-Life ...............................................................................................
`2.4 Studies in Patients with Duodenal Ulcer Disease or Zollinger-Ellison Syndrome
`
`
`2.5 Studies in Patients with Chronic Renal Disease ..........
`
`2.6 Relationship Between Plasma Concentration and Antisecretory Actiwty
`3. Therapeutic Trials ...................................................................................................................
`-.
`3.1 Treatment of Duodenal Ulcers ........................................................................................
`
`3.1. 1 Dose-Ranging Studies.
`'
`3.1.2 Open Studies .......................................
`
`3 l 3 Omeprazole Compared with Cimetidine or Raniltdine
`.............................
`
`3.2 Treatment of Ulcerative Peptic Oesophagitis ....................................
`'
`
`3.3 Treatment of' Gastric Ulcers ...............................................................
`
`3.4 Treatment of Zollittgerfillison Syndrome
`
`Side Effects and Effects on Laboratory Variables
`Drug Interactions ..............................................................................................................
`
`Dosage and Administration
`Place of Omeprazole in Therapy ...........
`.
`......................................................... -
`'.
`
`-':
`'
`
`.
`
` HE’S-“:5
`
`Summary
`
`is a substituted henzt‘mt‘dazole derivative which markedly i -
`Synopsis: Omeprazole'
`hibt'ts basal and stimulated gastric acid secretion. It has a unique mode of action. i _
`versibly blocking the so-called proton pump of the parietal cell which is supposedly t--
`terminal step in the acid secretoty pathway.
`in animals. on a weight basis. omeprazole is 2 to it] times more potent than cintetidi "
`in inhibiting gastric acid secretion. Toxicological studies in rats have shown that very
`doses of omeprazole administered for 2 years produce hyperplasia ofgattric enteroc ".
`mofit‘n—lt‘ke cells and carcinoids. a few with prolifitrotions into the submucosa. The s".
`nificance ofsuch findings to the clinical situation is wholly speculative and requires flirt
`.-
`research. Preliminary studies in patients with duodenal ulcers or Zollinger—Ellison s -
`drome have found no mucosal changes which would suggest that the drug represents
`risk for development ofcarcinoid tumours at therapeutic dosages.
`in patients with duodenal ulcers omeprozole. at dosages of at least 20mg once dai '_
`produced ulcer healing rates of between 60 and toast drier 2 weeks and between 90 .
`100% afier 4 weeks. even in patients resistant to treatment with Hrreceptor antagon ' u-
`Comparative trials clearly demonstrated that omeprazole 20 to 40mg administered 0 -r'
`daily was significantly more efective than usual dosage regimens ofcimett'dine and v
`-
`itidine in healing duodenal ulcers during 2 to 4 weeks of treatment. At present it
`a m
`are available evaluating omeprazole as maintenance therapy once ulcers have
`Other clinical trials have also shown that omeprazole is efl'ectivefor treating gastric ulc-- ‘
`ulcerative peptic oesophagitis. and ZollingerLEllison syndrome. In patients with Zollt'
`.-
`Ellison syndrome the profound and long lasting antisecretory activity of omeprazole
`make it the drug of choice for treating the massive acid hypersecretion associated wra
`the disease. especially when H‘s—receptor antagonists are inefl'ective. During clinical
`
`1
`
`“.Losec 'Lozec'. ‘Losek’ {AB Hassle. Astra; not yet commercially available}.
`
`Page 2
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`Page 2
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`

`

`
`
`reported to date omeprazole has been very well tolerated but further clinical experience is
`essential to fifty evaluate its safety profile.
`Thus. omeprazote represents a pharmacologicafly unique antisecretory drug which is
`very egfl'ective for rapidly healing peptic ulcers and peptic oesophagitis. and for reducing
`gastric acid hypersecretion in patients with Zoliinger—Ellisan 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-
`ment ofthese diseases.
`
`Pharmaoodynamie Studies: In vitro and in vivo animal studies demonstrated that ome-
`prazoie produces long lasting inhibition of gastric acid secretion which is likely due to
`non-competitive binding of a proton-activated derivative to parietal cell (H‘iKfl-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 mart (healthy volunteers and patients with duodenal ulcer dis-
`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 aner 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-
`sistent or as great as the effect on acid secretion. Omeprazole 0.35 tog/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 cmeprazole administered once daily usually resulted in ele-
`vated serum gastrin levels. Such hypergastrinaemia occurs secondary to a pronounced
`reduction of intragastric acidity, and returns to normal levels within 1
`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 antisecretory properties of
`omeprazole.
`Toxicological studies in rats have demonstrated that supramaximal doses of ome-
`prazole administered for long periods cause with: entemchromaffin—like cell hyperplasia
`and carcinoids, a few with proliferations into the suhmueosa. It has been summed 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.
`
`Pharmacoltinetic Studies: The absorption characteristics ofomeprazole are both fortn-
`ulation- and dose-dependent. Following administration of the drug as a buffeted oral
`solution, buffered encapsulated uncoated granules, or as caDSules of emetic-coated gran-
`ules, mean peak plasma omeprazole concentrations were attained after 20 minutes, 30
`minutes, and between 2 and 5 hours, reapectively. Interestingly, increased doses of ome-
`prazolc 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
`
`Page 3
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`u
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`Page 3
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`

`

`
`
`Omeprazole: A Preliminary Review
`
`1::‘
`
`
`
`.
`
`.
`
`'
`
`possibly indicate that the antisecretagogue improves its own absorption and relative bio-- .'
`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.
`Lfkg 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-
`changed drug has been recovered in the urine. Following absorption, 3 metabolites o -
`omeprazole have been identified: a sulphcne derivative, a sulphide derivative and hy-
`droxyomeprazole. Peal: 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 ofcapsules of enteriecoated granules. However;
`unidentified metabolites of omeprazole had a very similar plasma concentration-tin '.
`curve as the parent drug - in terms of peak concentration and the time to achieve it.
`Following administration of “C—omeprazole approximately 60% of total radioactivity is:
`recovered in the urine within 6 hours. Over a 4-day period about 80% of the administe -.. i
`dose was recovered in the urine and the remainder in the faeces. Total plasma clearance
`is relatively high (32 to 40 Mb) and most studies have reported a mean elimination half-1'
`life of omeprazole in healthy subjects of between 0.5 and 1.5 hours (usually about lij
`hour).
`_
`There are limited data available concerning the pharmacokinetic properties of ome-=
`prazole in patients with peptic ulcer disease or Zollinger-Ellison syndrome.
`The pharmacokinetic profile of omeprazole does not seem to be altered in patien .9
`with chronic renal failure and is not influenced by haemodialysis.
`Omeprazole plasma concentration does not correlate with its antisecretory activity a '
`a given time-point; indeed, the drug markedly inhibits acid secretion long after plas .
`'r
`concentrations have decreased below detection limits. However. there does seem to n v“
`a significant correlation between antisecretory activity and area under the plasma co. .
`centration-time curve.
`
`Therapeutic Trials: Clinical trials have demonstrated that omeprazcle at dosages n:
`at least 20mg once daily produces a duodenal ulcer healing rate of between 60 and II I '
`within 2 weeks and between 90 and 100% within 4 weeks. Base-finding studies sho a?
`that an optimal dosage of omeprazole is between 20 and 40mg once daily. Open clini~-:-'
`studies have confirmed these very high rates of duodenal ulcer healing even in a sat h'
`group of patients who were refractory to treatment with {dz-receptor antagonists (slot-.-
`or in combination with other antiulcer drugs). Appropriately designed comparative clini 9:
`trials clearly demonstrated that once-daily administration of omeprazole 20 to 40mg p . '
`duces significantly more rapid healing of duodenal ulcers afier 2 to 4 weeks of treatmen'
`than the Hz-receptor antagonists cimetidine and ranitidine. Additionally. omeprazole 2|
`'
`and 40mg once daily elicited significantly greater symptom relief than ranitidine 150 ----3
`twice daily, whereas in 2 other studies 30mg and 20mg of omeprazole were indisti
`:
`guishable from cimetidine 1000 mgiday and ranitidine 300 mgfday, respectively, in th'
`respect. Other clinical studies have shown that omeprazole administered once daily me i
`be effective for treating gastric ulcers and ulcerative peptic oesophagitis. Indeed. om'
`prazole 40mg once daily was significantly superior to ranitidine 150mg twice daily '..
`HS patients with reflux oesophagitis. Furthermore, in a double-blind multicentre t '-
`in “34 outpatients with gastric ulceration, omeprazcle 20mg once daily was as efi'ecti
`as ranitidine [50mg twice daily and healed 95% of gastric ulcers within 8 weeks.
`In patients with Zollinger-Ellison syndrome. omeprazole is a highly potent and 10w.
`acting antisecretagogue which many authors consider will become the drug of choice -:-
`controlling the massive acid hypersecretion associated with the disease. For patients wi
`r
`Zollinger—Ellison syndrome who are resistant to Hz-receptor antagonists. omeprazole i -"
`
`-
`
`Page 4
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`Page 4
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`

`
`
`-
`
`.- a: ole: A Preliminary Review
`
`[9
`
`fers a valuable therapeutic alternative to sumery (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-
`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 Zoflinger-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-
`ficient data are available for dosage recommendations in children.
`
`' . Pharmacodynamic Studies
`
`is a substituted benzimi-
`“-0: eprazole (fig. 1)
`- which markedly inhibits basal and stimu—
`
`'
`
`._ _'.-. gastric acid secretion in animals and man. It
`_'
`7
`.
`- first of a new class of antiulcer drugs likely
`‘_- introduced into clinical practice (it is not yet
`nercially available) and is thought to reduce
`'-__. secretion by inhibiting hydrogenfpotassium
`"W44 triphosphatase [(H+{K+)-ATPase], be-
`- to be the proton pump of the parietal cell.
`‘-.-' mechanism, at the terminal stage of the acid
`git-Eng process, means that for the first time in-
`t acidity can be reduced independent of the
`' of the primary stimulus. Since inhibition of
`'c acid is a most important indicator of the
`'1. .peutic potential of drugs used to treat peptic
`
`
`
`__I-'
`
`'. Structural tonnula of omeprazole.
`
`.
`
`Page 5
`
`ulceration, omcprazole might be expected to offer
`some advantages for the treatment of this disease.
`Independent of its clinical future, omeprazole is al-
`ready an important pharmacological ‘tool' for in-
`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
`
`Omeprazole
`
`Superficially, upper gaStrointestinal ulceration
`has a relatively simple underlying aetiology which
`involves some loss of ability of the mucosa to pro-
`tect against gastric acid andy‘or excessive secretion
`of acid. The complex morphological changes that
`occur with regard to mucosa] cytoprotection in re-
`lation to the various conditions found in the upper
`
`gut are currently poorly understood and drug treat-
`ment has been largely devoted to controlling lu-
`minal acidity (Bergiindh & Sachs 1985).
`Hydrochloric acid, one major cause of upper
`gastrointestinal tract ulcers, is secreted from par—
`ietal (oxyntic) cells by the gastric proton pump
`{gastric (HWKfl-ATPase], distal to cyclic adeno—
`sine monophosphate (cAMP), in response to at least
`3 different types of stimulation - cholinergic (va—
`gal), histaminergic and gastrinergic (Sachs 1984)
`[fig 2]. it follows that an individual antagonist to
`any one of the 3 (or more) receptor types will only
`
`Page 5
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`

`

`Omeprazole: A Preliminary Review
`
`Gastric {H*IK*}-ATPaso
`Inhibitors
`
`/ (9.9. omeprazolal
`
`Histamine fig-receptor antagonists
`(an. cimefldine and rsnltidlne}
`
`Fig. 2. A simple conceptual model of the parietal cell and some speculated mechanisms involved in the control and inhib'u'o .:
`gastric acid secretion [after Fiassa et al. 1984: Fimrriel s alum 1984: Lewin 1984: Reborn et ai. 1983}.- --brepresents pro-
`mechanisms by which certain ciesses of antiulcer drugs antagonise gastric acid stimulation.- —h indicates other additional 9
`of the Pia—receptor antagonists (although it is not necessarily at the receptor level) which may contribute to their antisecretcry av: "
`(tor a review see Bowman a Hand 1980}.
`
`partially block gastric acid secretion although there
`is evidence that the histamine—stimulated system
`may be dominant since histamine Hg-I'BOBDIOI' ant-
`agonists (cimetidine and ranitidine) seem capable
`of inhibiting a major portion of gastric acid secre-
`tion. However,
`inhibition of the gastric proton
`pump, probably the terminal stage of the acid se-
`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 a1. 1985; Larsson et al. 1985b)
`[fig 2].
`
`M.) Sire ofAcrr'on
`Parietal cells are buried deep within the
`mucosa (slightly beneath peptic cells). Their .-‘-
`tory surfaces are covered with microvilli and
`deeply invaginated to form channels termed w.
`aliculi. The gastric proton pump [(HVKS
`ATPase}, which has been discovered in frog (
`:I'
`set & Forte 1973), hog (Saccomani et al. 1975)
`human (Saccomani et a1. 1979) gastric mucosa,
`been isolated mostly from parietal cells altho -_
`there is some evidence that it may be present;
`jejunal (White 1985) and colonic (Gustin s: G
`man 1981) mucosa. In gastric mucosa the - u?
`
`Page 6
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`Page 6
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`

`I .. = ole: A Preliminary Review
`
`21
`
`7
`
`
`:u p is situated in the apical membrane and tub-
`' icles bordering the secretory canaliculi of the
`
`cell (for reviews see Berglindh & Sachs
`
`Olbe et a1. 1979}. Consequently, each can-
`us can be viewed as an invaginated extracel—
`compartment of low pH (about pH 1). Such
`environment should readily accumulate weak
`---. with a pKfl higher than the pH of the gastric
`
`partment
`(Berglindh & Sachs 1985; Sachs
`2'
`'3»: -)
`Omeprazole is a substituted benzimidazole and
`"--‘_weak base (pK,a = 3.97), which fulfills the criteria
`
`accumulation within the acid space (Brand-
`um ct a]. 1985). Animal studies have provided
`ng evidence that the main site of action of
`'
`imr urazole is indeed in the distal (to CAMP) por-
`.-... of the parietal cell. Thus, radiolabelled ome-
`--:
`-le administered intravenously to mice was
`to accumulate rapidly in gastric mucosa,
`, kidney, and in the choroid plexus, but after
`
`
`
`
`
`"
`
`_ hours high levels of radioactivity remained only
`the gastric mucosa. Autoradiography revealed
`it was localised in the parietal cells and sub-
`
`
`
`autoradiography
`electron microscopic
`_.-. nt
`-_.-;u onstrated that the radioactive label was almost
`
`.w usively found at the secretory surfaces and their
`-: : ediate vicinity. and in regions of cytoplasm
`
`taining the tubulovesicles (Helander et at. 1983,
`
`i— .- S).
`‘ -Fryklund et a]. (1984) using separated and en-
`'-'-_"|ed parietal and chief cell fractions from rabbit
`'
`n
`'c mucosa showed that omeprazole had a spe—
`inhibitory efl‘ect on acid secretion from par-
`cells and did not influence stimulated release
`
`
`
`x;
`I
`
`
`
`' pepsinogen from chief cells. However, Défize ct
`'
`(1935) found that omeprazole 0.1 mmoUL
`.. ungly stimulated secretion of preformed and re-
`
`---tly synthesised pepsinogen in isolated rabbit
`
`n
`'c glands even though it decreased pepsinogen
`. nesis. Similarly, Fimmel et a1. (1984) observed
`
`t orneprazole 0.1 mmollL stimulated pepsin re-
`:-- in the in vitro perfused mouse stomach model;
`
`mechanism remains uncertain although the in-
`
`does not seem to be due to a nonspecific
`- e e through disruption of chief cell membranes
`liken et al. 1935).
`
`i
`
`Page 7
`
`The above findings and those from additional
`in vitro experiments (see section 1.1.2) clearly in-
`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’U’Kfi-
`ATPase in the cytoplasm/tubulovesicles and secre-
`tory surfaces bordering the canaliculi. However,
`Keeling et aL (1985) and Beil and Hackbarth (1985)
`demonstrated that omeprazole also inhibits (Na’v‘
`K*)-ATPase isolated from dog kidneys, but to a
`lesser extent than its effects on (HWKfl-ATPase.
`The authors noted that the acidic compartments of
`the parietal cell would impart a high degree of se-
`lectivity onto omeprazole. Fin-titer 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-
`lyte or renal acid excretion in healthy volunteers.
`
`1.1.2 Mechanism of Action
`Various in vitro preparations ranging from iso-
`lated gastric mucosa to purified (H+;K+)~ATPase
`from parietal cells have been utilised to help define
`the mechanism of action of omeprazole (Wallmark
`et a1. 1983, 1985). As can be seen in table I, ome-
`prazole inhibits both basal and stimulated acid se-
`cretion (irrespective of whether acid formation was
`stimulated by histamine, cAMP, high K“ levels, or
`exogenously added ATP). In contrast, cimetidjne
`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-
`lated (H+[K+)~ATPase and withstood attempted
`reversal by antipyrine of its acid inhibitory prop-
`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-
`hanced in an acidic environment (Beil & Hack-
`barth 1985; Beil & Sewing 1985; Beil et ai. 1985;
`Im et a1. l985b,c; Keeling et a1. 1985; Wallrnark et
`al. 1983, 1934, 1985, 1986). This could be due to
`a change in parietal cell (HVKfi-ATPase making
`it more susceptible to the effects of omeprazole at
`
`Page 7
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`

`

`Omeprazole: A Preliminary Review
`
`Table i. Summary of in vitro studies designed to elucidate the mechanism of action of omeprazole, compared with cimetidina
`thiocyaoate as relerence drugs with regard to inhibition of gastric acid secretion (after Bail 8. Sewing 1984: Larssen s Fiyberg 1 2
`Larsson at al. 1984: Sewing et al. 1983: Wallmark et al. 1983. 1935)
`
`'__
`
`Inhihi‘IOf of 9881110 acid secretion
`
`ornaprazole
`
`cimetidine
`
`thiocyanate I
`
`—
`+
`r.
`
`—
`+
`-
`v
`
`-
`
`+
`-_
`
`_
`
`_
`
`+
`+
`
`+
`+
`+
`+
`
`+
`
`_
`
`+
`+
`+
`
`+
`+
`+
`+
`
`+
`
`+
`+
`
`+
`
`+
`
`+
`+
`
`|
`
`'
`
`Preparation
`
`Guinea~pig isolated gastric mucosa
`
`Rabbit isolated intact gastric glands
`
`Gastric acid
`stimulant
`
`Basal
`Histamine
`Dibutyryi-cAMP
`
`Basai
`Histamine
`Dibutyryi-CAMP
`K+
`
`Rabbit isolated permeable gastric glands
`
`ATP. Kt
`
`Rabbit isolated parietal cells
`
`Histamine
`DibutyryI-cAMP
`
`Pig isolated gastric [H‘iK‘HiTPase
`
`ATP. K+
`
`Guinea-pig (H‘Mfl-ATPase purified from
`parietai coils
`
`K+
`
`Guinea~pig isolated and enriched parietal Histamine
`cells
`DibutyryI-cAMP
`
`Abmw‘ations: cAMP = cyclic adenosine monophosphate: ATP = adencsine triphcsphate: + - drug produced inhibition of g .-
`acid secretion: — a drug did not produce any inhibition oi gastric acid secretion.
`
`.-
`
`low pH. However, at present, the weight of evi-
`dence suggests that omeprazole is activated at acidic
`pH (probably by protonation) and that the l-I+-ac-
`tivated derivative reacts with sulfhydryl groups as-
`sociated with gastric (HWKfl-ATPase {1111 et aI.
`1985b,c; Keeling et a].
`[985; Sewing & Harme-
`mann 1985; Wallmark et al. 1984). Beii and Sewing
`found that omeprazoie could inhibit various
`suifhydryl-oontaining ATPases but it was most ef—
`fective against gastric (Hfl'Kfl-ATPase. Thus, the
`unique low pH of the tubulovesicles should make
`the actions of omeprazoie very specific since ome-
`prazolc 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 (Im et al.
`
`1985c; Lorentmn et al. 1985; Rackur et at. 198
`Wailmark et al. 1986}. Wailmark et a1. (1986} .,
`centiy suggested that omeprazole acts in vi‘vo,
`:
`'
`'
`being converted in the acid compartments of
`.'
`parietal cell
`into a sulphenamide derivative,
`u.
`forming a disulphide complex with the e
`(HWKfi-A'I‘Pase. Alternatively, a sulphenic =n'_.
`form of omeprazole may react directly with the ....
`zyme. These proposed mechanisms differ
`.
`.
`those previously suggested by Irn et al. (1985c) .-.
`Rackur et at. (1985) and further studies are n'—'—- -,
`to elucidate the precise mechanisms involved
`the inactivation of gastric (HW‘Kfl-ATPase.
`There is some conflict regarding the nature i
`the omeprazoleflHflKfl-ATPase interaction.
`vitro studies have shown that the inhibitory e' m;
`of omeprazole can be washed out (Berglindh et :
`1985; Sewing et a1. 1983, 1985) or they can be
`versed by sulfliydryl-reducing compounds such
`
`'.
`
`Page 8
`
`Page 8
`
`

`

`-.-
`
`: ole: A Preliminary Review
`
`23
`
`._i.:.. uptoethanol. In vivo experiments demon-
`-I-I-I that omeprazole produces long lasting in—
`
`"n'tion of acid secretion which is likely due to ir-
`
`'ble inhibition of parietal cell
`(HVKfl-
`
`(Berglindh et al. 1985; Im et al. 1985a).
`__
`'.'-_ discrepancy between in vitro and in viva re-
`_",:It: needs to be explained, although there is evi-
`that omeprazole irreversibly inactivates (H's!
`)ATPase in vivo and new enzyme has to be syn-
`'--.-'sedI before gastric acid secretory activity can
`I restored (Ito et al. 1985a}.
`
`binds with (H+,’K+)-ATPase in the parietal cell. As
`a consequence of its long duration of action, re-
`peated once daily administration of omeprazole re-
`sulted in increased antisecretory activity which
`reached steady-state alter 5 days in the dog (Lars-
`son et al. 1985b).
`Thus. animal studies have clearly demonstrated
`that omeprazole is a potent inhibitor of gastric acid
`secretion and, reflecting its mode of action, it was
`equally active against various forms of gastric acid
`stimulation.
`
`"
`
`1.2 Effects on Gastric Acid Secretion
`
`1.2.2 Studies in Heaiihy Volunteers
`
`1L2.) Animai Studies
`
`Single-Dose Studies
`Omeprazole produced a dose-dependent inhi-
`bition of basal and stimulated (insulin, peptone, or
`pentagastrin) gastric acid secretion following oral
`administration of 20 to 90mg doses to healthy sub-
`jects (fig. 3). Since omeprazole degrades rapidly in
`water solution at low pH (Pilbraut 8r. Cederberg
`1985), various formulations have been developed
`to produce acceptable bioavailability following oral
`
`
`
`Fig. 3. Mean maximal percentage decrease in pentageatrln (III.
`I) or peptene {El} stimulated gastric acid secretion In groups of
`healthy volunteers administered oral omeprazole 20 to 90mg as
`single doses {after El Howden et al. 1984s: I Lind et el. 1983:
`E Londong at al. 1983).
`
`3
`
`__
`
`.
`
`F.
`
`The effectiveness of orneprazole in inhibiting
`#4 'c acid secretion has been investigated in con-
`_-.'nsI dogs with gastric fistulae or cannulated Hei-
`:i-I
`in pouches {Konturek et al. 1984a; Larson &
`.
`'van I984; Larsson et a1. 1983; Stachura et al.
`'1 3), in an ex vivo canine gastric chamber (larsen
`1984), in conscious rats with gastric fistulae
`.- .n et al. 1983), and in conscious guinea-pigs
`i ..
`.'-_:_. cannulae surgically implanted into the antral
`'-'_-=.u'on of the stomach (Batzri et al. 1984). In all
`nese studies omeprazole, whether administered
`E..-"I:1'I
`,
`intravenously.
`intraduodenally, or subcu-
`
`‘
`Iusly, dose-dependently inhibited basal and
`
`,IIrulated (histamine, pentagastrin, bethanechol)
`' acid secretion Omeprazole was found to be
`-. n 2 and 10 times more potent than the H2-
`I --_onist, cirnetidine, depending upon the route
`._ '.;i;-.-I
`inistration and the experimental model em-
`--."
`--.. (for a review see Larsson et al. 1985b).
`e potency of omeprazole following oral
`'='.. I ‘stration was generally less than its potency
`_".-.= given intravenously or intraduodenally. This
`. light to be due to its instability at low pH
`a
`I' Ig in reduced systemic availability (Larsson
`l985b). Somewhat surprisingly, considering
`'
`nort plasma elimination half-life (see section
`) omeprazole had a very long duration of ac
`in both dogs and rats (Larson & Sullivan
`_ ' Larsson et al. l985b). This accords with the
`.'_'Z .-,.._---.. mechanism of action of omeprazole (sec-
`I- 1.1.2) which suggests that the drug irreversibly
`
`;'
`_
`
`.. "_
`‘
`
`|
`.
`
`I
`
`Page 9
`
`Page 9
`
`

`

`
`
`
` qua O
`
`
`
`@
`
`
`
`
`
`
`
`
`D
`
`
`0)
`
`.3.
`
`N
`
`
`
`Acidmotion{mmcll15min]
`
`Omeprazole: A Preliminary Review
`
`administration. In single-dose studies omeprazole
`has been administered as an alkaline (sodium bi-
`carbonate) suspension (Lind et al. 1983; Utley et
`al. 1985b), as uncoated granules in capsules con-
`taining sodium bicarbonate (Londong et al. 1983)
`or as capsules of enteric-coated granules (Howden
`et al. 1984a).
`
`Omeprazole was found to have a long duration
`of action (the degree of acid inhibition remaining
`unchanged for at least 4 hours) which was signifi-
`cantly correlated to the area under the plasma con-
`centration-time curve (Lind et al. 1983; Londong
`et al. 1983). Indeed, Lind et al. (1933) showed that
`higher doses of omeprazoie produced significant
`inhibition of gastric acid secretion for 3 to 4 days
`(cg omeprazole 4