Drugs 32: I5-47 (I986)
`
`
`00! 2-6667/86/00070015/$16.50/0
`O ADIS Press Limited
`All rights reserved.
`
`Omeprazole
`A Preliminary Review of its Pharmaeodynamic and
`Pltarmacoltinetic 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. Bail, Abteilung Allgemeine Phar-
`
`makologie, Mcdizinische Hochschule Hannover, Hannover, W. Germany; T. Bcrgliedh,
`Center for Ulcer Research and Education. UCLA School of Medicine, Los Angelee, Col-
`ifornia, USA; J.D. Ganiur, Department of Health & Human Services, National Institute
`of Health. Bethesda. Maryland. USA; C.W. Handel, Department of Materia Medica,
`Stobhill General Hospital. Glasgow. Scotland; M.J.S. Langston, Department of There-
`peutics. University Hospital, Nottingham, England; W. Loudoeg, Modifiniscbe Klinik
`lnnenstadt, University of Munich, Munich, West Germany, D.W. Piper, Royal North
`Shore Hospital, St Leonards. New South Wales, Australia; R.E. Ponder, Academic De-
`partment of Medicine. The Royal Free Hospital. London, England; G. Socks, Center for
`Ulcer Research and Education, UCLA School of Medicine. Los Angeles. California, USA;
`K.-Fr. Sewing. Abteilung Allgemeine Pharmakolofie, Medizinisclle Hoehechule Han-
`nover. Hannover. W. Germany; E. Simon, Gastroenterologische Abteilung, Medizinische
`Universitatsklinik. Heidelberg, W. Germany; A. Wolu, Department of internal Medi-
`cine, University Hospital. Linkoping, Sweden; RJ. Watt, Department of Therapeutics,
`University Hospital. Nottingham, England; K.G. Wonulcy, Ninewells Hospital, Ninew-
`clls, Dundee, Scotland; MD. Yeontous, Department of Medicine, Austin Hospital. Hei-
`delberg, Victoria. Australia.
`
`Contents
`
`Summary ........
`........... . . .... ..... ..l6
`I. Phamtacodynatmc tudiea ..............m.....................
`.....l9
`
`l.I Site and Mechanism of Action ofonteprttzole ..
`.....l9
`l.l.l Site of Action ..........................................
`.....20
`l.l.2 Mechanism ofAction
`.....2l
`
`l.2 Effects on Gasuic Acid Secretio
`.....23
`1.2.! Animal studies ........................
`.....23
`l.2.2 Studies in Healthy Volunteer: ............................
`.....23
`l.2.3 Studies in Patients with Duodenal Ulcer Disease . . . . . .. . .. . .
`.. . ........ ..25
`1.2.4 Studies in Patients with Zollinger-Ellison Syndrome .......
`.....26
`L3 Effects on Other Gastric Juice Constituents ..... .............
`.....26
`l.3.l Pepsin ...................
`.....26
`1.3.2 Intrinsic Factor
`.....27
`L4 Effects on Gastrointestinal Hormones
`.....27
`l .4. I Serum Gastrin ................................................................
`
`
`
`Lupin Exh. 1024
`
`Lupin Exh. 1024
`
`

`
`Omeprazole: A Preliminary Review
`
`1.4.2 Other Gastrointestinal Honnones ..........................................................................
`L5 Effects on Gastric Emptying Rate .......
`L6 Effects on Endocrine Function
`l.7 Prevention of Experimental Gastric Muoosal Damage ............................................... ..
`
`1.8 Etfects on Gastric Mucosal Morphology .................................................... ..
`".
`l.9 Elfects on lntragastric Bacterial Activity and Nitrosamine Conoenuattons ................
`2. Pltarrnacoltinetic Studies ........................................................................................................3
`2.l Absorption. Plasma Concentrations. and Bioavailahility
`...3
`2.2 Distribution ...................................................................................................................
`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 Dismse ............................................................
`
`...3
`2.6 Relationship Between Plasma Concentration and Antisecretory Activity .
`3. Therapeutic Trials .................................................................................................... ..
`3.1 Treatment of Duodenal Ulcers
`.......................... ..
`3.l.l Dose-Ranging Studies ......
`......
`3.1.2 Open Studies .............
`3.1.3 Omcprazole Compared with Cimetidine or Ranitidine ..................................... ..
`3.2 Treatment of Uloerative Peptic Oesophagitis .........................
`3.3 Treatment of Gastric Ulcers ..........................
`3.4 Treatment of Zollinger-Ellison Syndrome
`Side Effects and Efiects on Laboratory Variables
`Drug Interactions .....................................................................................................................
`Dosage and Administration ........
`Place of Omeprazole in Therapy
`
`-
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`. -a- . .a .. . - -a - n.- .. - n.- c- . - -- ... - . . -- .- -s.. uu -u q - -~ano
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`"
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`
` #99?
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`Summary
`
`is a substituted benzimidazole derivative which markedly i
`Synopsis: 0meprazole'
`hibits basal and stimulated gastric acid secretion. It has a unique mode of action.
`i
`versibly blocking the so~caIled proton pump of the parietal cell which is supposedly
`terminal step in the acid secretory pathway.
`In animals, on a weight basis, omeprazoleis 2 to I0 times more potent than cimetid
`in inhibiting gastric acid secretion. Toxicological studies in rats have shown that very h ;
`doses of omeprazole administered for 2 years produce hyperplasia ofgastric enteroc
`maflin-like cells and carcinaids. a few with proltjferations into the submucosa. The ~
`ntjficance ofsuch findings to the clinical situation is wholly speculative and revuiresfim
`research. Preliminary studies in patients with duodenal ulcers or Zollinger-Ellison
`drome have found no mucosa! changes which would suggest that the drug repraents
`risk for development of carcinoid tumours at therapeutic dosaga.
`In patients with duodenal ulcers omeprazole. at dosages of at least 20mg once do’
`produced ulcer healing rates ofbetween 60 and 100% after 2 weeks and between 90 I
`v
`100% afier 4 weeks. even in patients resistant to treatment with Hz-receptor antagon'
`Comparative trials clearly demonstrated that omeprazale 20 to 40mg administered 0 »
`daily was significantly more effective than usual dosage regimens of cimetidine and w
`ilidine in healing duodenal ulcers during 2 to 4 weeks of treatment. At present no I
`are available evaluating omeprazole as maintenance therapy once ulcers have heal
`Other clinical trials have also shown that omeprazole is efi‘ectivefor treating gastric ult:
`ulcemtive peptic oesophagitis. and Zollirt'ger~Ellison syndrome. In patients with Zolli
`Ellison syndrome the profound and long lasting antisecretory activity of omatrazole
`;
`make it the drug of choice for treating the massive acid hypersecretion associated
`the disease. especially when H;-receptor antagonists are ineffective. During clinical t '
`
`«
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`I
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`‘Lo2ec', ‘Losek‘ (AB Hassle. Astra: not yet commercially available).
`
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`
`reported to date omeprazole has been very well tolerated but fitrtlter clinical experience is
`essential to fitlly evaluate its safety profile.
`Thus. omeprazole represents a pharrnacologically unique antisecretory dntg which is
`very eflective 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 mucosa! morphological changes during treatment with usual dose:
`in patients with peptic ulcer disease is confirmed it may be a major advance in the treat-
`ment of these diseases.
`
`Pharrnaeodynaulc Studies: In vitro and in vivo animal studies demonstrated that ome-
`Drazole produces long lasting inhibition of gastric acid secretion which is likely due to
`non-competitive binding of a protomictivated derivative to parietal cell (H*/K’)-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 lo times
`more potent than cimetidine 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 effect on acid secretion which appears to
`stabilise afler about 3 days. Short tenn 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, omcprazole reduces the total volume of
`ystric juice secreted and inhibits pepsin output. However. these changes are not as con-
`sistent or as great as the effect on acid secretion. Orncprazole 0.35 mg/kg administered
`intravenously did not significantly afiect 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 supramaxirnal doses of orne~
`prazole administered for long periods cause gastric enterodrromaflin-like cell hyperplasia
`and carcinoids. a few with proliferations into the subrnucosa. It has been suyestcd that
`hypergastrinaernia, 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.
`
`Plnrmaeoklnetlc Studies: The absorption characteristics ofomeprazole are both form-
`ulation- and dose-dependent. Following administration of the dmg as a butfered oral
`solution. buffered encapsulated uncoated granules, or as capsules of enteric-coated gran-
`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-
`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
`
`

`
`
`
`Omeprazole: A Preliminary Review
`
`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 decli —
`biexponentially. The apparent volume of distribution of omeprazole is about 0.3 to 0.,
`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 u
`changed dnrg has been recovered in the urine. Following absorption, 3 metabolites o
`omeprazole have been identified: a sulphone derivative, a sulphide derivative and h
`droxyomeprazole. Peal: plasma concentrations of the sulphone metabolite are attain
`shortly after those of unchanged omeprazole, 0.4 to 1.7 hours afier peak omepraz -
`concentrations following administration of capsules of enteric-coated granules. However
`unidentified metabolites of omeprazole had a very similar plasma concentration-ti I r
`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 '
`recovered in the urine within 6 hours. Over a 4-day period about 80% of the administe -
`dose was recovered in the urine and the remainder in the facccs. Total plasma clearan 3.
`is relatively high (32 to 40 L/h) and most studies have reported a mean elimination hal
`lil‘e of omeprazole in healthy subjects of between 0.5 and l.5 hours (usually about l
`hour).
`There are limited data available concerning the pharmacokinetic properties of o
`prazole in patients with peptic ulcer disease or Zollinger-Ellison syndrome.
`The pharmacokinetic profile of omeprazole does not seem to be altered in patien _
`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 afler plas ~
`concentrations have decreased below detection limits. However. there does seem to o
`a significant correlation between antisecretory activity and area under the plasma
`centration-time curve.
`
`-
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`I
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`‘
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`Tlienpeutic Trials: Cliniml trials have demonstrated that omeprazole at dosages
`at least 20mg once daily produces in duodenal ulcer healing rate of between 60 and l I I ‘
`within 2 weeks and between 90 and 100% within 4 weeks. Dose-finding studies sho --
`that an optimal dosage of omeprazole is between 20 and 40mg once daily. Open clini V
`studies have confirmed these very high rates of duodenal ulcer healing even in a sin ‘-'
`group of patients who were refractory to treatment with H;-receptor antagonists (alo ‘
`or in combination with other antiulcer drugs). Appropriately designed comparative clini I
`trials clearly demonstrated that once-daily administration of omeprazole 20 to 40mg p -
`duces significantly more rapid healing of duodenal ulcers alter 2 to 4 weeks of treatme
`than the H2-receptor antagonists cimetidine and
`Additionally. omeprazole I ~
`and 40mg once daily elicited significantly greater symptom relief than ranitidine I5 --
`twice daily, whereas in 2 other studies 30mg and 20mg of omeprazole were indisti
`'
`guishable from cimetidine 1000 mg/day and ranitidine 300 mg/day, respectively, in
`respect. Other clinical studies have shown that omeprazole administered once daily ma
`be effective for treating gastric ulcers and ulcerative peptic oesophagitis. Indeed, om
`prazole 40mg once daily was significantly superior to ranitidine lsomg twice daily '
`I78 patients with reflux oesophadtis. Furthermore. in a double-blind multioentre
`‘g
`in I84 outpatients with gastric ulceration. omeprazole 20mg once daily was as efiecti
`as ranitidine l50rng twice daily and healed 95% of gastric ulcers within 8 weeks.
`In patients with Zollinger-Ellison syndrome. omeprazole is a highly potent and I «_
`acting antisecretagogue which many authors consider will become the drug of choice I
`controlling the massive acid hypersecretiott associated with the disease. For patients wi-
`Zollinger-Ellison syndrome who are resistant to H1-receptor antagonists. omeprazole --I;
`
`-
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`

`
`.5 -
`
`le: A Preliminary Review
`
`I9
`
`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-
`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 scents 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 onreprazole dosage should
`be individualised so that the smallest dose is administered which reduces pstric acid
`secretion to less than 10 mm for the last hour before the next dose. At present. insuf-
`ficient data are available for dosage recommendations in children.
`
`1 , pyannagodyuamic smdigg
`
`'ep,-azole (fig 1) is 3 subsmmgd benzjmj.
`which markedly inhibits basal and stimu-
`U- gastric acid secretion in animals and man. It
`first of a new class of antiulcer drugs likely
`introduced imo cfinjca] pracucc (it is not ya
`.
`'_z ercially available) and is thought to reduce
`'« secretion by inhibiting hydrogen/potassium
`psine triphosphatase [(H*/K’)-ATPIISCI, b€-
`to be the proton pump of the parietal cell.
`‘mechanism. at the terminal stage of the acid
`"1'! 2 DIOCCSS, means that for the first time in-
`'° 3°l‘“‘Y '3“ be "°d“°°d i“d°P°“d““ °f ‘h°
`of the primary stimulus. Since inhibition of
`flild is 8 most important indicator of the
`- utic potential of drugs used to treat peptic
`
`..-
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`. Lstructural formula of omeprazola.
`
`ulceration, orneprazole might be expected to offer
`some advantages for the treatment of this disease.
`Independent of its clinical future, omeprazole is al-
`ready an} important tvharmacolysical ‘tool’ for in-
`Vestlsatlns Dhyslolostcnl find blofihelnlcal chances
`that 00¢“ in 91¢ $133175‘? ml"-7°38 and f0!’ evaluanns
`the mechanisms ofaction of gastric acid inhibitors.
`
`1,] site and Mechanism of Action of
`Omeprazole
`
`superficially’ upper gasunintesfinal ulceration
`has a relatively simple underlying aetiology which
`involves some loss of ability of the mucosa to pro-
`am against gastric acid and”, excessive notation
`of acid. The complex morpholofiml changes that
`occur with "sud to mucosa] cywpmtecfion in ,.e_
`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-
`rninal acidity (Berglindh &. Sachs I985).
`Hydrochloric acid, one major cause of upper
`gastrointestinal tract ulcers, is secreted from par-
`ietal (oxyntic) cells by the gastric proton pump
`[gastric (Ht/K*)-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
`
`

`
`Omcprazolez A Preliminary Review
`
`Gastric (I-I"/K‘)-ATPQQQ
`lnhblton
`/ (0.9. omepruole)
`
`/
`
`(0.9. clmetldlne and ranllldlne)
`
`jsorou——+|4—Pauoui ooI?>|4——Muoou-——
`
`Fla. 2. A simple conceptual model of the parietal cell and some speculated mechanisms involved in the control and lnhlb‘ -
`gastric acid secretion (alter Fiasse et al. 1984: l-‘immel 8 Blum 1984: Lewin 1984; Flabon et ei. 1983).— -—-brepresems -
`- - -
`mechanisms by which certain classes of antlulcer drugs antagonise gastric acid slimulatlon.— -5 Indicates other additional e i
`of the H,-receptor antagonists (although it is not necessarily at the receptor level) which may contribute to their antleecretory :
`(tor a review see Bowman at Hand 1980).
`
`~
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`panially block gastric acid secretion although there
`is evidence that the histamine-stimulated system
`may be dominant since histamine H2-receptor ant-
`agonists (cimetidine and ranitidine) scent capable
`of inhibiting a major portion of gastric acid secre-
`tion. However,
`inhibition of the gastric proton
`pump, probably the temiinal 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
`I985; Helander et al. 1985; Larsson et al. 1985b)
`[fig. 2].
`
`1.1.] Site of Action
`Parietal cells are buried deep within the ;v
`mucosa (slightly beneath peptic cells). Their
`tory surfaces are covered with microvilli and ‘=
`deeply invaginated to form channels tenned -
`aliculi. The gastric proton pump [(H*/K
`ATPase], which has been discovered in frog(
`ser & Forte 1973), hog (Saocomani et al. 1975)
`human (Saccomani et al. 1979) pstric mucosa,
`been isolated mostly from parietal cells alth
`there is some evidence that it may be present
`
`jejunal (White 1985) and colonic (Gustin 8:.
`man 1981) mucosa. In gastric mucosa the -
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`'1" -~
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`2 ole: A Preliminary Review
`
`u p is situated in the apical membrane and tub-
`-. 'cles bordering the secretory canaliculi of the
`_
`4 =
`cell (for reviews see Berglindh & Sachs
`5: Olbe et al. 1979). Consequently, each can-
`’~
`: can be viewed as an invaginated extracel-
`- compartment of low pH (about pH 1). Such
`environment should readily accumulate weak
`—: with a pK, higher than the pH of the gastric
`partment
`(Berglindh & Sachs
`I985; Sachs
`
`_
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`s
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`Orneprazole is a substituted benzimidazole and
`-1 -: base (pK,, = 3.97). which fulfills the criteria
`j accumulation within the acid space (Brand-
`m et al.
`l98S). Animal studies have provided
`'ng evidence that
`the main site of action of
`»
`to
`2 ole is indeed in the distal (to cAMP) por-
`of the parietal cell. Thus. radiolabelled ome-
`~v le administered intravenously to mice was
`‘-
`-
`to accumulate rapidly in ustric mucosa,
`'
`-
`. kidney. and in the choroid plexus. but afier
`,~- hours high levels of radioactivity remained only
`the gastric mucosa. Autoradiography revealed
`it was localised in the parietal cells and sub-
`
`r... - t electron microscopic autoradiography
`' _-.. nstrated that the radioactive label was almost
`' in nsively found at the secretory surfaces and their
`'
`-n iate vicinity. and in regions of cytoplasm
`. m 'gthe tubulovesiclesfl-lelander et al. l983.
`:5 : 5),
`
`t
`
`A Pryklund et al. (I984) using separated and en-
`-
`- -« parietal and chief cell fractions from rabbit
`in ‘c mucosa showed that omeprazole had a spe-
`.
`inhibitory effect on acid secretion from par-
`cells and did not influence stimulated release
`
`.
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`.
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`’
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`1
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`' pepsinogen from chief cells However, Defize et
`I (I985) found that omeprazole 0.l mmol/L
`ngly stimulated secretion of preformed and re-
`am y synthesised pcpsinogen in isolated rabbit
`
`'c glands even though it decreased pepsinogen
`=
`'
`”_w-s esis. Similarly, Fimmel et al. (I984) observed
`' omeprazole 0.1 mmol/L stimulated pepsin re-
`~
`in the in vilro perfused mouse stomach model;
`mechanism remains uncertain although the in-
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`does not seem to be due to a nonspecific
`- through disruption of chief cell membranes
`etal. 1985).
`
`The above findings and those from additional
`in virro experiments (see section l.l.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*/K*)-
`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“/
`K*)-ATPase isolated from dog kidneys. but to a
`lesser extent than its effects on (1-1*/K*)-ATPase.
`The authors noted that the acidic compartments of
`the parietal cell would impart a high degree of se-
`lectivity onto omeprazole. Further evidence for the
`specificity of action of omeprazole is provided by
`Howden and Reid (1984) who reported that the
`dmg had no demonstrable elfects on renal electro-
`lyte or renal acid excretion in healthy volunteers
`
`1.1.2 Mechanism ofAction
`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 al. I983, l985). As can be seen in table l. ome-
`prazole inhibits both basal and stimulated acid se-
`cretion (irrespective ofwhether 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 (l-l*/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 eflects.
`The potency of omeprazole is markedly en-
`hanced in an acidic environment (Beil & Hack-
`barth l985; Beil & Sewing l985; Beil el al. I985;
`lm et al. l985b,c; Keeling et al. 1985; Wallmark et
`al. 1983, 1984, 1985, 1986). This could be due to
`a change in parietal cell (I-1*/K‘)-ATPase making
`it more susceptible to the efiects of omeprazole at
`
`

`
`Omeprazole: A Preliminary Review
`
`Table I. Summary oi In vltro studies designed to elucidate the mechanism oi action of omeprazole. compared with eimetidine
`thiocyanate as reierence drugs. with regard to inhibition of gastric acid secretion (after Bell 5 Sewing 1984; Larseon & Flyberg 1 = --‘
`Larsson 3! al. 1984: Sewing et al. ‘I933: Walmflk 8! al. 1983. 1985)
`
`Inhibitor of gastric acid sedation
`
`OMOWBIOIO
`
`cimetidine
`
`INOCYGHIIO
`
`-
`+
`_
`
`-
`+
`’
`-
`
`-
`
`+
`_
`
`-
`
`_
`
`4-
`4-
`
`+
`+
`+
`+
`
`+
`
`-
`
`4»
`+
`+
`
`+
`+
`+
`+
`
`+
`
`+
`+
`
`4.
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`+
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`+-
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`0-
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`Preparation
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`Guinea-pig ‘solated gastric mucosa
`
`Rabbit isolated intact gastric glands
`
`Rabbit isolated permeable gastric glands
`Rabbit isolated parietal eels
`
`Gastric acid
`stimulant
`
`Basal
`Histamine
`Dibutyryl-cAMP
`
`Basal
`Histamine
`Dibutyryl-CAMP
`K4
`
`ATP. K’
`Histamine
`Dibutyryl-CAMP
`
`Pig isolated gastric (l-l‘/l<‘)—ATPase
`
`ATP. K‘
`
`Guinea-pig (H’/K’)-ATPase punlied lrom
`parietal cells
`
`K’
`
`Guinea-pig isolated and enriched parietal Histamine
`cells
`Dlbutyryl-CAMP
`
`Abbrevialoris: cAMP = cyclic adenosine monophosohate: ATP = adenosine trlphosphale: + - drug produced inhibition of go i
`acid secretion: - - drug dd not produce any Inhibition ol 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 H*-ac-
`tivated derivative reacts with sullhydryl groups as-
`sociated with gastric (l-1*/K*)-ATPase (Im et al.
`l985b,c: Keeling et al. 1985: Sewing & Hanna-
`mann 1985; Wallmarlr et al. 1984). Beil and Sewing
`found that omeprazole could inhibit various
`sulthydryl-containing ATPases but it was most ef-
`fective against gastric (H*/K*)-ATPase. Thus. the
`unique low pH of the tubulovesicles should make
`the actions of omeprazole very specific since ome-
`prazole preferentially accumulates at these low pH
`sites and an acid pH is necessary to activate the
`drus
`A number of research groups have performed
`more detailed studies to detennine the structure of
`the active form of omeprazole and the nature of
`its reaction with gastric (H*/K‘)-A'I'Pase (lm et al.
`
`1985c; Lorentzon et al. 1985; Rackur et al. I98
`Wallmark et al. i986). Wallmark et al. (1986)
`'
`oently suggested that omeprazole acts in vivo,
`:
`being converted in the acid compartments 0 :-
`
`»
`
`into a sulphenamide derivative, -
`parietal cell
`forming a disulphide complex with the e
`(I-l*/K")-A'I'Pase. Alternatively. a sulphenic =-
`form of omeprazole may react directly with the «.
`zyme. These proposed mechanisms differ
`-
`'
`I
`those previously suggested by lm et al. (l985c) V
`Rackuret al. (1985) and further studies are -
`to elucidate the precise mechanisms involved '
`the inactivation of gastric (H*/K*)-ATPase.
`There is some eonflict regarding the nature =
`the omeprazole/(H*/K‘)-ATPase interaction.
`r
`vitro studies have shown that the inhibitory e - v.
`of omeprazole can be washed out (Berglindh et
`l
`1985: Sewing et al. 1983, I985) or they can be -
`versed by sullhydryl-reducing compounds such
`
`

`
`I
`
`--2 : ole: A Preliminary Review
`
`23
`
`4-» -«ptoethanol. In vivo experiments demon-
`'- -n-- that omeprazole produces long lasting in-
`'- ‘on of acid secretion which is likely due to ir-
`i
`« 'ble inhibition of parietal cell
`(H*/K")-
`(Berglindh et al. 1985; lm et al. 1985a).
`discrepancy between in vltro and in viva re-
`_'3- needs to be explained. although there is evi-
`‘_ -
`that omeprazole ineversibly inactivates (H*/
`.ATPase in vivo and new enzyme has to be syn-
`- -- before gastric acid secretory activity can
`tored (lm 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 afler 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, retlecting 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 Healthy Volunteers
`
`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 & Cedcrbeig
`I985), various formulations have been developed
`to produce acceptable bioavailability following oral
`
`E i E E F
`
`ig. 3. Mean maximal percentage decrease in pentagastrln (D.
`I) or peptone (El) stimulated gastrlc ecld secretion In groups of
`healthy volunteers admlnlstered oral omeprazole 20 to 90mg as
`single doses (alter U Houden et al. 19343: I um et al. 1963:
`I3 Londong at al. 1903).
`
`.2.) Animal Studies
`The efiectiveness of omeprazole in inhibiting
`.~- 'c acid secretion has been investigated in con-
`s dogs with gastric fistulae or cannulated Hei-
`in pouches (Konturek et al. 1984a; Larson &
`_.u
`“: ‘van 1984; Larsson et al. I983; Stachura et al.
`
`’'
`
`7‘.‘I 3). in an ex vivo canine gastric chamber (Larsen
`“'
`1984), in conscious rats with gastric fistulae
`»: n et al. i983), and in conscious guinea-pigs
`in cannulae surgically implanted into the antral
`» ‘n of the stomach (Batzri et al. 1984). In all
`';u -
`studies omeprazole. whether administered
`H ‘u
`, intravenously, intraduodenally, or subcu-
`H -« sly, dose-dependently inhibited basal and
`lated (histamine, pentagastrin, bethanechol)
`~- c acid secretion. Omeprazole was found to be
`t-»
`2 and 10 times more potent than the H2-
`‘
`4 onist, cimetidine, depending upon the route
`in . ‘nistration and the experimental model em-
`-
`« (for a review see Larsson et al. l98Sb).
`" e potency of omeprazole following oral
`'nistration was generally less than its potency
`-1 given intravenously or intraduodenally. This
`a nu ;
`t to be due to its instability at low pH
`:
`- g in reduced systemic availability (Larsson
`1985b). Somewhat surprisingly, considering
`_
`" -- r
`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
`
`. -- mechanism of action of omeprazole (sec-
`'
`’~ 1.1.2) which suggests that the drug irreversibly
`
`

`
`
`
`Omeprazole: A Preliminary Review
`
`
`
` dC
`
`
`
`
`
`administration. In single-dose studies omeprazole
`has been administered as an alkaline (sodium bi-
`carbonate) suspension (Lind et al. I983; Utley et
`al. 1985b). as uncoated granules in capsules con-
`taining sodium bicarbonate (Londong et al. I983)
`or as capsules of enteric-coated granules (Howden
`et al.
`l984a).
`
`
`
`
`
`
`
`Acidaecmtlon(rrmol/15min)
`
`toA
`
`variously) stimulation in 6 healthy subjects treated once -
`with oral omeprazote 15mg (E) or placebo (U) for 5 days.
`.
`urementa were made 2 hours after administration on days 1
`and 5 (after Lind at al. 1983).
`
`administration of omeprazole results in an in
`mg inhibitory action on gastric acid secretion, s-_
`bilising after about 3 days (Lind et al. 1983; M‘ ;
`et al. 1985).
`
`Further studies in which oral omeprazole( .
`_‘
`ally enteric—coated granules) S to 60mg once -
`.
`was administered for periods of between 5 and. '
`
`.
`'
`days have generally confirmed the findings of
`et al. (I983); for a review see Cederberg at al. (19
`[table 11]. Overall, the results from these s
`-'
`
`indicate that the optimal once daily dosage ofo -x
`prazole is 20 to 30mg for reduction of acid .
`tion; producing almost complete inhibition »
`maximally stimulated gastric acid sec