`
`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
`
`
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`_ Omeprazole: A Preliminary Review
`
`,;
`1.4.2 Other Gastrointestinal Hormones
`"
`1.5 Effects on Gastric Emptying Rate
`
`3.
`1.6 Effects on Endocrine Function ........................................................................................
`'
`1.? Prevention of Experimental Gastric Muoosal Damage
`
`1.8 Effects on Gastric Mucosa] Morphology ........
`
`1.9 Effects on Intragastric Bacteria] Activity and Ntttosamine Concentrations ..
`2. Pharmacokinetic Studies ......................................................................................................... 3
`2. I Absorption. Plasma Concentrations, and Bioavailability ..............................................3
`22 Distribution
`...3.
`
`2.3 Metabolism and Excretion ..
`I
`2.3.1 Elimination Half-Life ...............................................................................................
`2.4 Studies in Patients with Duodenal Ulcer Disease or anlinger-Ellison Syndrome
`
`
`2.5 Studies in Patients with Chronic Renal Disease ..........
`
`2.6 Relationship Between Plasma Concentration and Antisecretory Actiwty
`3. Therapeutic Trials ...................................................................................................................
`-'.
`3.] Treatment of Duodenal Ulcers ........................................................................................
`
`3.1. l Dose-Ranging Studies.
`'
`3.1. 2 Open Studies .......................................
`
`
`3 l 3 Omeprazole Compared with Cimetidine or Ranittdine
`.............................
`3.2 Treatment of Ulcerative Peptic Oesophagitis ....................................
`'
`
`3.3 Treatment of Gastric Ulcers ...............................................................
`
`3.4 Treatment of anlingerfillison Syndrome
`Side Effects and Effects on Laboratory Variables .........................................................
`
`Drug Interactions ..............................................................................................................
`
`Dosage and Administration
`Place of Omeprazote in Therapy ...........
`.
`......................................................... -
`'.
`
`-';
`'
`
`.
`
` HE’S-"i“
`
`Stratum):
`
`is a substituted benzimidazole derivative which markedly i -
`Synopsis: Omeprazole'
`hibits 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 secretory pathway.
`in animals. on a weight basis. omeprazoie is 2 to to 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 of gastric enteroc -.
`mafiin—like cells and carcinoids. a few with proliferations into the submttcosa. 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 omeprazole. at dosages of at least 20mg once dai '_
`produced ulcer healing rates of between 60 and toast alier 2 weeks and between 90 :
`_
`100% afier 4 weeks. even in patients resistant to treatment with Hrreceptor antagon ' .,'.
`Comparative trials clearly demonstrated that omeprazole 20 to 40mg administered 0-r
`daily was significantly more efi'eciive than usual dosage regimens ofct'mett'dine and v
`-
`itidine in healing duodenal ulcers during 2 to 4 weeks of treatment. At present it
`, m’
`are available evaluating omeprazole as maintenance therapy once ulcers have heal--__.
`Other clinical trials have also shown that omeprazole is efi'ectivefor treating gastric ulc-- ‘
`ulcerative peptic oesophagitis. and Zollinger—Eihson syndrome. in patients with Zollt'n.
`Ellison syndrome the profound and long lasting antisecretory activity of omeprazole
`make it the drug of choice for treating the massive acid hypersecretion associated
`the disease. especially when Jig—receptor antagonists are ingfi'ective. During clinical
`
`l
`
`“.I..osec 'Lozec'. ‘Losek’ {AB Hassle. Astra; not yet commercially available}.
`
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`reported to date omeprazoie has been very welt tolerated but further ciinicai experience is
`essentiai to fiiiiy evaluate its safety profile.
`Thus. omeprazole represents a pharmacologicaily unique antisecretory drug which is
`very eflective for rapidly healing peptic ulcers and peptic oesophagitis. and for reducing
`gastric acid hypersecretion in patients with Zoiiinger-Eilison syndrome. if the apparent
`absence of undesirable mucosa! morphoiogicai changes during treatment with usual doses
`in patients with peptic ulcer disease is confirmed. it may be a major advance in the treat-
`ment of these 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 cirnetidine on a weight basis.
`Single-dose studies in man (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 reflect on acid secretion which appears to
`stabilise after about 3 days. Short term studies indicate that 20 to 302113 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 trig/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-
`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 suprarnaximal doses of ome-
`prazole administered for long periods cause manic entemchromaflin—tike 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 ofomeprazole are both form-
`ulation- and dose-dependent. Following administration of the drug as a buffered oral
`solution, buffered encapsulated unconted granules, or as capitoles of emetic-coated gran-
`ules, mean peak plasma omeprazole concentrations were attained after 20 minutes, 30
`minutes, and between 2 and 5 hours, rettpectively. Interestingly, increased doses of ome-
`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
`
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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 omeprazole 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 ofomeprazole 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. omeprazcle 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, omeprazole 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 Inn;
`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 -"
`
`-
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`.- a: ole: A Preliminary Review
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`[9
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`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.
`
`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
`
`.
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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?
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`_._-.
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`.. = ole: A Preliminary Review
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`21
`
`" u p is situated in the apical membrane and tub-
`'
`
`»:icles bordering the secretory canaliculi of the
`
`_
`cell (for reviews see Berglindh & Sachs
`I'
`'5; 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
`'_.-,.‘.I: -)
`Omeprazole is a substituted benzimidazole and
`i'i-fiweak base (pK,a = 3.97), which fulfills the criteria
`accumulation within the acid space (Brand-
`
`-__ in et a]. 1985). Animal studies have provided
`'
`as evidence that the main site of action of
`
`i_.:n ' 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
`"
`
`i 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 naively found at the secretory surfaces and their
`
`-. : ediate vicinity. and in regions of cytoplasm
`
`u taining the tubulovesicles (Helander et al. 1983,
`
`.3 5)_
`I -Fryklund et a]. (1984) using separated and en-
`'-'-_"|ed parietal and chief cell fractions from rabbit
`'
`.
`'c mucosa showed that omeprazole had a spe—
`inhibitory effect on acid secretion from par-
`: cells and did not influence stimulated release
`
`_
`
`
`
`
`
`
`-pepsinogen from chief cells. However, Défize ct
`--
`(1985) found that omeprazole 0.1 mmolfL
`-. ungly stimulated secretion of preformed and re-
`g-tly synthesised pepsinogen in isolated rabbit
`n
`'c glands even though it decreased pepsinogen
`. nesis. Similarly. Fimtnel et a1. (1984) observed
`x;
`15:1 omeprazole 0.1 mmollL stimulated pepsin re-
`‘1
`:-- 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
`.-
`‘ligfiesze et al. 1935).
`
`‘
`
`I.
`
`Page 7
`
`The above findings and those from additional
`in vitrc 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‘
`Kfl-ATPase isolated from dog kidneys, but to a
`lesser extent than its effects on (H+fK+)-ATPase.
`The authors noted that the acidic compartments of
`the parietal cell would impart a high degree of se-
`lectivity onto omeprazole. Flu-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, cimetidine
`only antagonised histamine-stimulated gastric acid
`secretion which is consistent with its H2~receptor
`blocking properties. Omeprazole and thiocyanate
`shared many common pharmacodynamic actions,
`although only omeprazole directly inhibited iso-
`lated (HWKfl-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 8!. Sewing 1985; Beil et al. 1985;
`Int et a1. l985b,c; Keeling et a1. 1985; Wallrnark et
`a1. 1983, 1984, 1985, 1986). This could be due to
`a change in parietal cell (HVKfl-ATPase making
`it more susceptible to the effects of omeprazole at
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`Omeprazole: A Preliminary Review
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`Table l. Summary of in vitro studies designed to elucidate the mechanism of action of omeprazote, compared with cirnetidine
`thiocvanate as reterence drugs with regard to inhibition of gastric acid secretion (after Beil 8. Sewing 1984: Larsson s Ftvberg 1 2
`Larsson et at. 1984: Sewing et al. 1983: Wallmark et al. 1983. 1935)
`
`'__
`
`Preparation
`
`Guinea~pig isolated gastric mucosa
`
`Rabbit isolated intact gastric glands
`
`Gastric acid
`stimulant
`
`Basal
`Histamine
`Dibutyryi-cAMP
`
`Basai
`Histamine
`Dibutyryt-CAMP
`K+
`
`Rabbit isolated permeable gastric glands
`
`ATP. Kt
`
`Flabbit isolated parietal cells
`
`Histamine
`DioutyryI-cAMP
`
`Pig isolated gastric [H‘fKfi-ATPase
`
`ATP. K+
`
`Guinea-pig (H‘Mfl-ATPase purified from
`parietat cells
`
`10
`
`Guinea-pig isolated and enriched parietal Histamine
`cells
`DihutyryI-cAMP
`
`Inhlhl‘IOf of gastric acid secretion
`
`orneprazole
`
`cimetidtne
`
`thiocyanate I
`
`—
`+
`._
`
`-
`+
`-
`v
`
`—
`
`+
`-_
`
`_
`
`_
`
`+
`+
`
`+
`+
`+
`+
`
`+
`
`_
`
`+
`+
`+
`
`+
`+
`+
`+
`
`+
`
`+
`+
`
`+
`
`+
`
`+
`+
`
`r
`
`|
`
`'
`
`Abbreviations: cAMP = cystic adenosine monophosphate: ATP = adenosine triphosphate: + 2 drug produced inhibition of g .-
`acid secretion: — = drug did not produce any Inhibition or gastric acid secretion.
`
`t
`
`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 (H+/K+)-ATPase (Im at al.
`1985b,c; Keeling et al. 1985; Sewing & Hanne-
`mann 1985; Wallmark et al. 1984). Beil and Sewing
`found that omeprazole could inhibit various
`sulthydryl-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 omeprazole very specific since ome-
`prazolc preferentially accumulates at these low pH
`sites and an acid pH is necessary to activate the
`dmg.
`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; Lorentzon et at. 1985; Rackur et at. 198
`Wallmark ct al. 1986}. Wallrnark et a1. (1986)
`cently suggested that omeprazole acts in vr'vo,
`:
`being converted in the acid compartments of
`.'
`parietal cell
`into a snlphenamide derivative,
`forming a disulphide complex with the on: u.
`(HWKfl-ATPase. Alternatively, a sulphenic an?
`form of omeprazole may react directly with the ....
`zyme. These proposed mechanisms differ
`.
`.
`those previously suggested by 111: 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 omepmzoleflHVKfl-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 sulfltydryl-reducing compounds such
`
`'.
`
`I
`
`Page 8
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`Dr. Reddy's EXh. 1029
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`Dr. Reddy's Exh. 1029
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`

`

`"
`
`-.-
`
`: ole: A Preliminary Review
`
`23
`
`in vivo experiments demon-
`-_.'.-I-II raptoethanol.
`:'.:;.-.. that omeprazole produces long lasting in—
`_'II"tion of acid secretion which is likely due to ir-
`
`"
`'ble inhibition of parietal cell
`(HVKfl-
`
`__
`(Berglindh et al. 1985; Im et al. 1985a).
`1._ discrepancy between in vitra and in viva re-
`_"III: needs to be explained, although there is evi-
`"jI_-._I -- that omeprazole irreversibly inactivates (Ht;r
`)ATPase in vivo and new enzyme has to be syn-
`"-.-I:'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 after 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.
`
`'"
`
`.12 Effects on Gastric Acid Secretion
`
`1.2.2 Studies in Heaiihy Volunteers
`
`_-I.2.l Animai Studies
`The effectiveness of omeprazole in inhibiting
`I
`'c acid secretion has been investigated in con-
`on dogs with gastric fistulae or cannulated Hei-
`:iI
`.in pouches {Konturek et al. 1984a; Larson 8:.
`'van I984; Larsson et a1. 1983; Stachura et al.
`.; 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
`..
`
`-T;-II cannulae surgically implanted into the antral
`'.__'=.u'on of the stomach (Batzri et al. 1984). In all
`IIese studies omeprazole, whether administered
`E.-."‘I:1'Iy,
`intravenously.
`intraduodenally, or subcu-
`
`Insly, dose-dependently inhibited basal and
`
`outdated (histamine, pentagastrin bethanechol)
`'___ ' acid secretion Omeprazole was found to be
`I n 2 and 10 times more potent than the H2-
`=.I; Lonist, cirnetidine. depending upon the route
`._ Zita-t
`inistration and the experimental model em-
`__I.
`--II (for a review see Larsson et al. 1985b).
`'. Ie potency of omeprazole following oral
`I I stration was generally less than its potency
`'.-.. given intravenously or intraduodenally. This
`' ught to be due to its instability at low pH
`!
`I .3 in reduced systemic availability (Larsson
`l985b). Somewhat surprisingly, considering
`2:;'--:=-Iort plasma elimination half-life (see section
`'-
`13-. 1) omeprazole had a very long duration of ac
`'
`in both dogs and rats (Larson & Sullivan
`..
`' Larsson et al l985b) This accords with the
`‘_.-
`1.__._-I I..-.I mechanism of action of omeprazole (sec-
`.
`_I- l. l .2) which suggests that the drug irreversibly
`
`_
`
`-'
`
`.
`'
`
`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 (Pilbrant & Cederberg
`1985), various formulations have been developed
`to produce acceptable bioavailability following oral
`
`
`
`Fig. 3. Mean maximal percentage decrease in pentagaatrln (III.
`I) or peptone {El} stimulated gastric acid secretion In groups of
`heatflry volunteers administered oral omeprazcle 20 to 90mg as
`single doses {after El Howden et al. 1984s: I Lind et el. 1983:
`a Londong at at. 1983).
`
`Page 9
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`
`Dr. Reddy's Exh. 1029
`
`

`

`a" O
`
`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 a1. 1983)
`or as capsules of enteric-coa