Drugs 32: IS-47 (1986)
`0012~7/86/fXXJ7-001.5/S16 . .50/0
`C> ADIS Press limited
`All riahts reserved.
`
`Omeprazole
`A Preliminary Review of its Pharmacodynamic and
`Pbarmacokinetic Properties, and Therapeutic Potential in
`Peptic Ulcer Disease and Zollinger-Eillson Syndrome
`
`Stephen P. Clisso/d and Deborah M. Campo/i-Richards
`ADIS Drug Information Services, Auckland
`
`Various sections of the manuscript reviewed by: Jf'. Jkil, Abteilung Allgemeine Phar(cid:173)
`makologie, Medizinische Hochschule Hannover, Hannover, W. Germany; T. Bnwl/tul/1,
`Center for Ulcer Research and Education, UCLA School of Medicine, Los Angeles. Cal(cid:173)
`ifornia, USA; J.D. Gt1nlur, Department of Health & Human Services, National Institute
`of Health, Bethesda, Maryland, USA; C. W. Howdtfl, Depanment of Materia Medica,
`Stobhill General Hospital, Glasgow, Scotland; M.J.S. Llllfgmllfl, Department of Thera(cid:173)
`pcuti s. Uni ersity Hospital, Nottingham, England; W. Lo11do,g, Medizinische Klioik
`lnnenstadt, University of Munich, Munich, West Germany; D.W. Pipu, Royal Nonh
`Shore Hospital. St Leonards New South Wales Australia· R.E. Poulfller, Academic De(cid:173)
`partment of Medicine, The Royal Free Hospital, London, England; G. Saclu, Center for
`Ulcer Rese.arch and Education, U LA School of Medicine, Los Angeles, California USA;
`K.-Fr. Sewl,g, Abtcilung Allgemeine Pharmakologie, Medizinisclu: Hochschule Han(cid:173)
`nover, Hannover, W. Germany; B. Simofl, Gastroeoterologische Abt.eiluog, Medizinisch
`Uni cr iUUsklinik Heidelberg, W. Germany: A. Wtlhue, Depanment of fntemal Medi(cid:173)
`ci ne, University Hospital Lin_koping, Sweden; R.P. Walt, Department of Therapeutics,
`University Hospital, Nottingham, England; K.G. Wormsley, Ninewells Hospital, Ninew(cid:173)
`ells, Dundee Scotland; N.D. Yeonuuu, Department of Medicine, Austin Hospital, Hei(cid:173)
`delbeJB, Victoria, Australia.
`
`Co11t111ts
`
`Summary ....................................................................................................................................... 16
`I. Pharmacodynamic Studies ...................................................................................................... 19
`1.1 Site and Mechanism of Action of Omeprazolc .............................................................. 19
`1.1.1 Site of Action ........................................................................................................... 20
`1.1.2 Mechanism of Action .............................................................................................. 21
`I .2 Effects on Gastric Acid Secretion .................................................................................... 23
`1.2.1 Animal Studies ......................................................................................................... 23
`1.2.2 Studies in Healthy Volunteers ................................................................................ 23
`1.2.3 Studies in Patients with Duodenal Ulcer Disease ................................................ 25
`1.2.4 Studies in Patients with Zollinger-Ellison Syndrome ........................................... 26
`1.3 Effects on Other Gastric Juice Constituents .................................................................. 26
`1.3.1 Pepsin ........................................................................................................................ 26
`1.3.2 Intrinsic Factor ......................................................................................................... 27
`1.4 Effects on Gastrointestinal Hormones ............................................................................ 27
`1.4.1 Serum Gastrin .......................................................................................................... 27
`
`CFAD EXIDBIT 1040
`
`

`
`Omeprazole: A Preliminary Review
`
`1.4.2 Other Gastrointestinal Hormones .............................................................. ............ 28
`1.5 Effects on Gastric Emptying Rate ................................................................................... 28
`1.6 Effects on Endocrine Function ........................................................................................ 21
`I. 7 Prevention of Experimental Gastric Mucosal Damage ................................................. 2
`1.8 Effects on Gastric Mucosal Morphology ........................................................................ 29
`1.9 Effects on Intragastric Bacterial Activity and Nitrosamine Concentrations ................ 3l
`2. Pharmacokinetic Studies ........................................................................................................ .31
`2.1 Absorption. Plasma Concentrations, and Bioavailability .............................................. 31
`2.2 Distribution ............................................................................................... ........................ )~
`2.3 Metabolism and Excretion ............................................................................................. ..
`2.3.1 Elimination Half-Life ............................................................................................... 34
`2.4 Studies in Patients with Duodenal Ulcer Disease or Zollinger-EUison Syndrome ..... )~
`2.5 Studies in Patients with Chronic Renal Disease ............................................................ )~
`2.6 Relationship Between Plasma Concentration and Antisecretory Activity ................... )~
`3. Therapeutic Trials ................................................................................................................... 3S
`3.1 Treatment of Duodenal Ulcers ............................................. ........................................... 36
`3. 1.1 Dose-Ranging Studies ... ........................................................................................... 36
`3. 1.2 Open Studies .......................................................................................................... ..
`3. 1.3 Omeprazole Compared with Cimetidine or Ranitidine ....................................... 37
`3.2 Treatment of Ulcerative Peptic Oesophagitis ................................................................ .
`3.3 Treatment of Gastric Ulcers ............................................................................................ 39
`3.4 Treatment of Zollinger-Ellison Syndrome ...................................................................... 39
`4. Side Effects and Effects on Laboratory Variables ................................................................ 40
`5. Drug Interactions ..................................................................................................................... 41
`6. Oosaae and Administration .................... ............................................................................... .42
`7. Place of Omeprazole in Therapy ........................................................................................... 42
`
`Syaopsl.s: Omeprazole1 is a substituJed benzimidazole derivative which markedly ;,.
`hibits basal and stimulated gastric acid secretion. It has a unique mode of action. irn
`versibly blocking the so-called proton pump of the parietal cell which is supposedly I
`terminal step in the acid secretory pathway.
`In animals, on a weight basis, omeprazole is 2 to 10 times more potent than cimetidi
`in inhibiting gastric acid secretion. Toxicological studies in rats have shown that very hi
`doses of omeprazole administered for 2 years produce hyperplasia of gastric enterociJro(cid:173)
`maffin-like cells and carcinoids. a few with proliferations into the submucosa. The si
`nificance of such findings to the clinical situation is wholly speculative and requires fimh
`research. Preliminary studies in patients with duodenal ulcers or Zo/linger-E//ison sy~t­
`drome have found no mucosal changes which would suggest that the drug represents
`risk for development of carcinoid tumours at therapeutic dosages.
`In patients with duodenal ulcers omeprazole, at dosages of at least 20mg once daily,
`produced ulcer healing rates of between 60 and 10096 qfter 2 weeks and between 90 a
`100% after 4 weeks, even in patients resistant to treatment with H rreceptor antagoni l$.
`Comparative trials clearly demonstrated that omeprazole 20 to 40mg administered on
`daily was signijicamly more effective than usual dosage regimens of cimetidine and ran.
`itidine in healing duodenal ulcers during 2 to 4 weeks of treatment. At present no daJ
`are a~·ailable evaluating omeprazole as maintenance therapy once ulcers have healttl.
`Other clinical trials have also shown that omeprazole is effective for treating gastric ulcm.
`ulcerative peptic oesophagi/is, and Zo/linger-EIIison syndrome. In patients with Zollinger(cid:173)
`EI/ison syndrome the profound and long lasting antisecretory activity of omeprazo/e mq
`make it the drug of choice for treating the massive acid hypersecretion associated wit
`the disease, especially when Hrreceptor antagonists are inejfeclive. During clinicaltrialt
`
`I
`
`'Losee', 'lozec'. 'losek' (AB Hassle, Astra; not yet commercially available).
`
`

`
`17
`
`reported to date omeprazole has been very well tolerated but further clinical experience is
`essential to fully evaluate its safety profile.
`Thus, omeprazole represents a pharmacologically unique ant/secretory drug which is
`very e.ffective for rapidl.v healing peptic ulcers and peptic oesophagitis. and for reducing
`gastric acid hypersecretion in patients with Zollinger-EIIison 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 of these diseases.
`
`Pharmacodynamic Studies: In vitro and in vivo animal studies demonstrated that ome(cid:173)
`prazole produces long lasting inhibition of gastric acid secretion which is likely due to
`non-competitive binding of a proton-activated 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 10 times
`more potent than cimetidine on a weight basis.
`Single-dose studies in man (healthy volunteers and patients with duodenal ulcer dis(cid:173)
`ease or Zollinger-EIIison syndrome) have shown that omeprazole inhibits both basal and
`stimulated gastric acid secretion in a dose-dependent manner. Following repeat once daily
`administration, omeprazole has an increasing effect on acid secretion which appears to
`stabilise after about 3 days. Short term studies indicate that 20 to 30mg once daily is the
`optimum dosage regimen in healthy volunteers and patients with duodenal ulcer disease
`in remission; this virtually abolishes gastric acidity within 6 hours and reduces stimulated
`acid output after 24 hours by 60 to 70%.
`In addition to its effects on gastric acidity, omeprazole reduces the total volume of
`gastric juice secreted and inhibits pepsin output. However, these changes are not as con(cid:173)
`sistent or as great as the effect on acid secretion. Omeprazole 0.35 mgfkg administered
`intravenously did not significantly affect basal or stimulated intrinsic factor secretion.
`Furthermore, omeprazole does not seem to have any significant influence on gastric
`emptying rate, or on the majority of gastrointestinal hormones- apart from gastrin. Short
`periods of treatment with omeprazole administered once daily usually resulted in ele(cid:173)
`vated serum gastrin levels. Such hypergastrinacmia occurs secondary to a pronounced
`reduction of intragastric acidity, and returns to normal levels within I to 2 weeks of
`stopping treatment.
`Orally, but not parenterally, administered omeprazole seems to be cytoprotective in
`some animal models of peptic ulcer disease such as Shay ulcers, stress-induced ulcers,
`and ulcers induced by various necrotising agents. The mechanisms involved are not fully
`understood but appear to be independent of the established antisecretory properties of
`omeprazole.
`Toxicological studies in rats have demonstrated that supramaximal doses of ome(cid:173)
`prazole administered for long periods cause gastric enterochromaffin-like 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.
`
`Pharmacoklnetic Studies: The absorption characteristics of omeprazole are both form(cid:173)
`ulation- and dose-dependent. Following administration of the drug as a buffered oral
`solution, buffered encapsulated uncoated granules, or as capsules of enteric-coated gran(cid:173)
`ules, mean peak plasma omeprazole concentrations were attained after 20 minutes, 30
`minutes, and between 2 and 5 hours, respectively. Interestingly, increased doses of ome(cid:173)
`prazole produced disproportionately larger increases in mean peak plasma concentration
`and systemic availability. Similarly, repeat once daily administration for 5 to 7 days
`resulted in significant elevations of mean peak plasma concentration and area under the
`plasma concentration-time curve. Since omeprazole is acid labile, these findings could
`
`

`
`Omeprazole: A Preliminary Review
`
`It
`
`possibly indicate that the antisecretagogue improves its own absorption and relative bio(cid:173)
`availability by inhibiting acid secretion. An alternative explanation involves saturation
`of enzymes responsible for the first-pass metabolism of omeprazole.
`Following intravenous administration omeprazole plasma concentrations decline
`biexponentially. The apparent volume of distribution of omeprazole is about 0.3 to 0.4
`L/kg which is compatible with localisation of the drug in extracellular water. Penetration
`of omeprazole into red blood cells is low, whereas its plasma protein binding is high -
`between 95 and 96% in human plasma.
`Omeprazole is eliminated rapidly and almost completely by metabolism; no un(cid:173)
`changed drus bas been recovered in the urine. Followins absorption, 3 metabolites of
`omeprazole have been identified: a sulphone derivative, a sulphide derivative and hy(cid:173)
`droxyomeprazole. Peak plasma concentrations of the sulpbone metabolite are attained 1
`shortly after those of unchanged omeprazole, 0.4 to 1.7 hours after peak omeprazole 1
`concentrations followins administration of capsules of enteric-coated granules. However,
`unidentified metabolites of omeprazole had a very similar plasma concentration-time
`curve as the parent drug - in terms of peak concentration and the time to achieve iL
`Following administration of '4C-omeprazole approximately 60% of total radioactivity is
`recovered in the urine within 6 hours. Over a 4-<lay period about 80% of the administered
`dose was recovered in the urine and the remainder in the faeces. Total plasma clearance 1
`is relatively high (32 to 40 L/h) and most studies have reported a mean elimination half·
`life of omeprazole in healthy subjects of between 0.5 and 1.5 hours (usually about I
`hour).
`There are limited data available concerning the pharmacokinetic properties of ome-
`prazole in patients with peptic ulcer disease or Zollinger-Eilison syndrome.
`The pbarmacokinetic profile of omeprazole does not seem to be altered in patientS
`with chronic renal failure and is not influenced by haemodialysis.
`Omeprazole plasma concentration does not correlate with its antisecretory activity at
`a given time-point; indeed. the drus markedly inhibits acid secretion long after plasma
`concentrations have decreased below detection limits. However, there does seem to be
`a significant correlation between antisecretory activity and area under the plasma con(cid:173)
`centration-time curve.
`
`1
`
`1
`
`Thenpeudc Trials: Clinical trials have demonstrated that omeprazole at dosages of
`at least 20mg once daily produces a duodenal ulcer bealin& rate of between 60 and I~
`within 2 weeks and between 90 and 100% within 4 weeks. Dose-finding studies howed
`that an optimal dosage of omeprazole is between 20 and 40mg once daily. Open cJjnical
`studies have confirmed these very high rates of duodenal ulcer healing even in a small
`group of patients who were refractory to treatment with H2-receptor antagonists (alone
`or in combination with other antiulcer drug:;). Appropriately designed companltive clinical
`trials clearly demonstrated that once-daily administration of omeprazole 20 to 40mg pro(cid:173)
`duces significantly more rapid healing of duodenal ulcers after 2 to 4 weeks of treatment
`than the H2-receptor antagonists cimetidine and ranitidine. Additionally, omeprazole lOrna
`and 40mg once daily elicited significantly greater symptom relief than ranitidine 150m&
`twice daily, whereas in 2 other studies 30mg and 20mg of omeprazole were indistin(cid:173)
`guishable from cimetidine 1000 mg/day and ranitidine 300 mg/day, respectively, in this
`respect. Other clinical studies have shown that omeprazole administered once daily may
`be effective for treatins gastric ulcers and ulcerative peptic oesophagitis. Indeed, ome(cid:173)
`prazole 40mg once daily was significantly superior to ranitidine 150mg twice daily in
`178 patients with reflux oesophagitis. Furthermore, in a double-blind multicentre trial
`in 184 outpatients with gastric ulceration, omeprazole 20mg once daily was as effective
`as ranitidine 150mg twice daily and healed 95% of gastric ulcers within 8 weeks.
`In patients with Zollinger-Ellison syndrome, omeprazole is a highly potent and lon&
`acting anti secretagogue which many authors consider will become the drug of choice for
`controlling the massive acid hypersecretion associated with the disease. For patients with
`Zollinger-EUison syndrome who are resistant to H2-receptor antagonists, omeprazole of·
`
`

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

`
`Omeprazole: A Preliminary Review
`
`Antlmuscartntc druga
`(e.g. plrenzeplne)'
`
`' ..
`1
`l Gastrin
`/
`)
`-----I~
`Jl
`( Histamine > / 1f
`~
`
`/
`
`/
`Hlatamlne Hrreceptor antagonlata
`(e.g. c:lmetldlne and ranltldlne)
`
`Oal1rtc (H+/1(+)-ATPaM
`""~
`/(e.g. omeprazole)
`
`I
`
`-I
`------·tt+
`
`__.;.-+-------· K+
`
`-oooo+------.....o~•cr
`
`---Serosa--• <~~~>----Parietal c:el----t•HI+--Mucou-
`
`Fig. 2. A simple conceptual model or the parietal cell and some speculated mechanisms Involved in the control and Inhibition
`gastric acid secretion (alter Fiasse et al. 1984; Flmmel & Blum 1984; Lewin 1984; Rabon et si. 1983).- -~represents pro
`mechanisms by which certain classes or antiulcer drugs antagonise gastric acid stimulation.- .... Indicates other additional e
`ot the H2-receptor antagonists (although it Is not necessarily at the receptor level) which may contribute to their antisecretofy
`(for a review see Bowman & Rand 1980).
`
`partially block gastric acid secretion although there
`is evidence that the histamine-stimulated system
`may be dominant since histamine Hrreceptor ant(cid:173)
`agonists (cimetidine and ranitidine) seem capable
`of inhibiting a major portion of gastric acid secre(cid:173)
`tion. However, inhibition of the gastric proton
`pump, probably the terminal stage of the acid se(cid:173)
`creting pathway from the parietal cell, provides a
`means of blocking gastric acid secretion by a greater
`amount. This is the proposed site and mechanism
`of action of omeprazole (Berglindh & Sachs
`1985; Helander et al. 1985; Larsson et al. 1985b)
`[fig. 2).
`
`1.1.1 Site of Action
`Parietal cells are buried deep within the
`mucosa (slightly beneath peptic cells). Their
`tory surfaces are covered with microvilli and
`deeply invaginated to form channels termed
`aliculi. The gastric proton pump [(H+ !K
`A TPase ], which has been discovered in frog (G
`ser & Forte 1973), hog (Saccomani et al. 1975)
`human (Saccomani et al. 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 & G
`man 1981) mucosa. In gastric mucosa the pro
`
`

`
`Qmeprazole: A Preliminary Review
`
`21
`
`pomp is situated in the apical membrane and tub(cid:173)
`alovesicles bordering the secretory canaliculi of the
`;arleta! cell (for reviews see Berglindh & Sachs
`J985; Olbe et al. 1979). Consequently, each can(cid:173)
`aliculus can be viewed as an invaginated extracel(cid:173)
`hllar compartment of low pH (about pH I). Such
`tft environment should readily accumulate weak
`Iiies with a pKa higher than the pH of the gastric
`compartment (Berglindh & Sachs 1985; Sachs
`1984).
`Omeprazole is a substituted benzimidazole and
`a weak base (pK .. = 3.97). which fulfills the criteria
`Cor accumulation within the acid space (Brand(cid:173)
`ltrtlm et al. 1985). Animal studies have provided
`ltrong evidence that the main site of action of
`omeprazole is indeed in the distal (to cAMP) par(cid:173)
`lion of the parietal cell. Thus, radiolabelled ome(cid:173)
`prazole administered intravenously to mice was
`shown to accumulate rapidly in gastric mucosa,
`liver, kidney. and in the choroid plexus, but after
`16 hours high levels of radioactivity remained only
`in the gastric mucosa. Autoradiography revealed
`that it was localised in the parietal cells and sub(cid:173)
`ICQUent electron microscopic autoradiography
`demonstrated that the radioactive label was almost
`aclusively found at the secretory surfaces and their
`immediate vicinity, and in regions of cytoplasm
`containing the tubulovesicles (Helander et al. 1983,
`1985).
`Fryklund et al. (1984) using separated and en(cid:173)
`riched parietal and chief cell fractions from rabbit
`pstric mucosa showed that omeprazole had a spe(cid:173)
`cific inhibitory effect on acid secretion from par(cid:173)
`ietal cells and did not influence stimulated release
`of pepsinogen from chief cells. However. Defize et
`aL (1985) found that omeprazole 0.1 mmol/L
`itrongly stimulated secretion of preformed and re(cid:173)
`cently synthesised pepsinogen in isolated rabbit
`pstric glands even though it decreased pepsinogen
`synthesis. Similarly, Fimmel et al. ( 1984) observed
`that omeprazole 0.1 mmol/L stimulated pepsin re(cid:173)
`lease in the in vitro perfused mouse stomach model;
`abe mechanism remains uncertain although the in(cid:173)
`crease does not seem to be due to a nonspecific
`leakage through disruption of chief cell membranes
`(Defize et al. 1985).
`
`The above findings and those from additional
`in vitro experiments (see section 1.1.2) clearly in(cid:173)
`dicate that the main site of action of omeprazole
`is in the parietal cell at a point distal to cAMP. It
`seems likely that the drug binds with (H+ /K +)(cid:173)
`A TPase in the cytoplasm/tubulovesicles and secre(cid:173)
`tory surfaces bordering the canaliculi. However,
`Keeling et al. ( 1985) and Beil and Hackbarth ( 1985)
`demonstrated that omeprazole also inhibits (Na+/
`K +)-A TPase isolated from dog kidneys, but to a
`lesser extent than its effects on (H+ /K +)-ATPase.
`The authors noted that the acidic compartments of
`the parietal cell would impart a high degree of se(cid:173)
`lectivity onto omeprazole. Further evidence for the
`specificity of action of omeprazole is provided by
`Howden and Reid ( 1984) who reported that the
`drug had no demonstrable effects on renal electro(cid:173)
`lyte or renal acid excretion in healthy volunteers.
`
`1.1.2 Mechanism of Action
`Various in vitro preparations ranging from iso(cid:173)
`lated gastric mucosa to purified (H+;K•)-ATPase
`from parietal cells have been utilised to help define
`the mechanism of action of omeprazole (Wall mark
`et al. 1983, 1985). As can be seen in table I, ome(cid:173)
`prazole inhibits both basal and stimulated acid se(cid:173)
`cretion (irrespective of whether acid formation was
`stimulated by histamine, cAMP, high K+ levels, or
`exogenously added A TP). In contrast, cimetidine
`only antagonised histamine-stimulated gastric acid
`secretion which is consistent with its H 2-receptor
`blocking properties. Omeprazole and thiocyanate
`shared many common pharmacodynamic actions,
`although only omeprazole directly inhibited iso(cid:173)
`lated (H+ /K +)-A TPase and withstood attempted
`reversal by antipyrine of its acid inhibitory prop(cid:173)
`erties in isolated gastric mucosa. These findings
`highlight the late stage in the acid secreting process
`at which omeprazole exerts its inhibitory effects.
`The potency of omeprazole is markedly en(cid:173)
`hanced in an acidic environment (Beil & Hack(cid:173)
`barth 1985; Beil & Sewing 1985; Beil et al. 1985;
`lm et al. 1985b,c; Keeling et al. 1985; Wallmark et
`al. 1983. 1984, 1985, 1986). This could be due to
`a change in parietal cell (H+ /K +)-A TPase making
`it more susceptible to the effects of omeprazole at
`
`

`
`Omeprazole: A Preliminary Review
`
`I
`T•ble I. Summary of In vitro studies designed to elucidate the mechanism of action of omeprazole, compared with clmetldine a
`thiocyanate as reference drugs, with regard to inhibition of gastric acid secretion (after Bell & Sewing 1984; Larsson & Ryberg 1~
`Larsson et al. 1984; Sewing et al. 1983; Wallmark et al. 1983, 1985)
`
`Preparation
`
`Guinea-pig isolated gastric mucosa
`
`Rabbit isolated Intact gastric glands
`
`Gastric acld
`stimulant
`
`Basal
`Histamine
`Dibutyryl-cAMP
`
`Basal
`Histamine
`DibutyrykAMP
`K•
`
`Rabbit isolated permeable gastric glands ATP, K•
`
`Rabbit Isolated parietal cells
`
`Histamine
`Dibutyryl-cAMP
`
`Pig isolated gastric (W/K•)-ATPase
`
`ATP, K•
`
`Guinea-pig (W/K•)-ATPase purified from
`parietal cells
`
`K•
`
`Guinea-pig isolated and enriched parietal Histamine
`cells
`Dibutyryl-cAMP
`
`Inhibitor of gastric acid secretion
`
`omeprazole
`
`cimetldlne
`
`thiocyanate
`
`+
`+
`
`+
`+
`+
`+
`
`+
`
`+
`
`+
`
`+
`
`+
`+
`+
`
`+
`+
`+
`+
`+
`
`+
`+
`+
`
`+
`
`+
`+
`
`Abbreviations: cAMP = cyclic adenosine monophosphate; ATP 3 adenosine triphosphate: + • drug produced Inhibition of gas
`acid secretion; -
`• drug did not produce any Inhibition of gastric acid secretion.
`
`low pH. However, at present, the weight of evi(cid:173)
`dence suggests that omeprazole is activated at acidic
`pH (probably by protonation) and that the H+ -ac(cid:173)
`tivated derivative reacts with sulfhydryl groups as(cid:173)
`sociated with gastric (H+ /K +)-A TPase (1m et al.
`1985b,c; Keeling et al. 1985; Sewing & Hanne(cid:173)
`mann 1985; Wall mark etal. 1984 ). Beil and Sewing
`found
`that omeprazole could
`inhibit various
`sulfhydryl-containing A TPases but it was most ef(cid:173)
`fective against gastric (H+ /K +)-A TPase. Thus, the
`unique low pH of the tubulovesicles should make
`the actions of omeprazole very specific since ome(cid:173)
`prazole preferentially accumulates at these low pH
`sites and an acid pH is necessary to activate the
`drug.
`A number of research groups have performed
`more detailed studies to determine the structure of
`the active form of omeprazole and the nature of
`its reaction with gastric (H+ /K +)-ATPase (1m et al.
`
`t 985c; Lorentzon et al. 1985; Rackur et al. 198S
`Wallmark et al. 1986). Wallmark et al. (1986)
`cently suggested that omeprazole acts in vivo, aft
`being convened in the acid compartments of
`parietal cell into a sulphenamide derivative,
`forming a disulphide complex with the eozym
`(H+ /K +)-A TPase. Alternatively, a sulphenic adcl
`form of omeprazole may react directly with the
`zyme. These proposed mechanisms differ fro
`those previously suggested by Im et al. ( 1985c) anct 1
`Rackur et al. ( 1985) and further studies are needed
`to elucidate the precise mechanisms involved ·
`the inactivation of gastric (H+ /K +)-A TPase.
`There is some conflict reprding the nature
`the omeprazole/(H+ /K +)-ATPase interaction. Ill
`vitro studies have shown that the inhibitory effi
`of omeprazole can be washed out (Berglindh et aL
`1985; Sewing et al. 1983, 1985) or they can be roo
`versed by sulfhydryl-reducing compounds such
`
`

`
`Oineprazole: A Preliminary Review
`
`23
`
`eercaptoethanol. In vivo experiments demon(cid:173)
`
`ted that omcprazole produces long lasting in(cid:173)
`tion of acid secretion which is likely due to ir(cid:173)
`~eversible inhibition of parietal cell (H+ /K +)-
`ATPase (Berglindh et al. 1985; lm et al. 1985a).
`The discrepancy between in vitro and in vivo re(cid:173)
`IUits needs to be explained, although there is evi(cid:173)
`dcoce that omeprazole irreversibly inactivates (H • 1
`}-A TPase in 1•ivo and new enzyme has to be syn(cid:173)
`ised before gastric ac.id secretory activity can
`be restored (lm ct al. 1985a).
`
`binds with (H+ /K +)-ATPase in the parietal cell. As
`a consequence of its long duration of action, re(cid:173)
`peated once daily administration of omeprazole re(cid:173)
`sulted in increased antisecretory activity which
`reached steady-state after 5 days in the dog (Lars(cid:173)
`son et at. 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 Healthy Volunteers
`
`1.2. 1 Animal Studies
`The effectiveness of omeprazole in inhibiting
`pstric acid secretion has been investigated in con(cid:173)
`jcious dogs w