Gut, 1984, 25, 707-710
`
`Effects of single and repeated doses of omeprazole on
`gastric acid and pepsin secretion in man
`
`C W HOWDEN, J A H FORREST, AND J L REID
`
`From the University Department of Materia Medica and Gastroenterology Unit, Stobhill General Hospital,
`Glasgow
`
`SUMMARY The effects of omeprazole, a substituted benzimidazole, on gastric acid and pepsin
`secretion have been studied in twelve healthy subjects. From six to eight hours after a single oral
`dose of 30 mg, there was a 66% reduction in basal acid output, and a 71·2% reduction in
`pentagastrin stimulated acid output. A single dose of 60 mg produced a 91· 7% reduction in basal
`acid output and a 95·3% reduction in pentagastrin stimulated acid output. After seven days
`treatment with 30 or 60 mg daily, there was almost 100% inhibition of both basal and
`pentagastrin stimulated acid output. Omeprazole did not significantly affect pepsin secretion
`which is in keeping with its proposed mode of action, as an inhibitor of the H + /K +-A TPase
`enzyme on the secretory membrane of the parietal cell. There were no side effects after
`omeprazole either with single or repeated dosing.
`
`The substituted benzimidazoles are new agents
`which are potent inhibitors of gastric acid secretion.
`They act by selective, non-competitive inhibition of
`the H+1K+-ATPase enzyme in the parietal cell. 1
`This enzyme is the active transport mechanism for
`hydrogen ion secretion in the stomach. Although
`one of these agents, omeprazole, has been shown to
`suppress basal and pentagastrin stimulated acid
`secretion after a single dose/ little is known about
`its effects after repeated dosing. In addition,
`previous studies have used a buffered suspension of
`the drug2 as it is partially inactivated by gastric acid,
`or have looked at its acid inhibitory effect 24 hours
`after a dose. 3
`We have studied the effects of two different doses
`of omeprazole on basal and pentagastrin stimulated
`acid and pepsin secretion after a single dose and
`after seven days of treatment. Capsules of enteric(cid:173)
`coated omeprazole granules were used, and the
`effects studied around the time of expected
`maximum acid inhibition.
`
`Methods
`
`(range 19-34 years) were studied. None had any
`past medical history of note or was on any
`medication. All subjects gave informed written
`consent to the study which was approved by the
`research and ethical committee of the Greater
`Glasgow Health Board, Northern District.
`Subjects were randomly allocated to one of two
`groups. Each received one dose of placebo followed
`after three to five days by either 30 mg or 60 mg of
`omeprazole orally as a single daily dose for seven
`days. Subjects attended the Clinical Pharmacology
`Research Laboratory on three occasions during the
`study: day 0 (placebo); day one (first dose omepra(cid:173)
`zole) and day seven (seventh dose omeprazole). The
`study design was identical on each occasion.
`Subjects arrived fasted at around 0830 hours and
`were given capsules containing enteric-coated
`omeprazole granules or placebo. A standard light
`breakfast was given 15 minutes after drug admini(cid:173)
`stration and the subject remained fasted for the
`remainder of the study day. At around 1415 hours
`(or 5~ hours postdose) a size 16 FG vented nasa(cid:173)
`gastric tube was passed and its position checked by
`means of a water recovery technique. 4 From 1430
`until 1530 hours - that is, from six to seven hours
`postdose - gastric juice was aspirated continuously
`and collected as four 15 minute samples for
`measurement of basal acid output. During the next
`hour, each subject received an intravenous infusion
`of pentagastrin (1·2 JLg/kg/h), and gastric juice was
`707
`
`SUBJECTS
`Twelve healthy male subjects, mean age 25·2 years
`
`Address for correspondence: Dr C W Howden. Deparlment of Materia
`Medica. Stobhill General Hospital. Glasgow G21 3UW. Scotland.
`Received for publication 29 July 1983
`
`

`
`708
`
`Howden, Forrest, and Reid
`
`continuously aspirated and collected as four 15
`minute samples for determination of plateau acid
`output.
`the acid
`Basal acid output was defined as
`produced in the second half of the basal hour
`multiplied by a factor of two,5 and plateau acid
`output as the acid produced in the two consecutive
`highest 15 minute periods of the second hour
`multiplied by a factor of two. An intravenous
`infusion of pentagastrin was used to give a constant
`rate of stimulation , and the dose selected was
`designed to give a near maximal stimulus without
`producing systemic side effects. 6 Acid output was
`determined by titration to pH 7 ·0 with 0·1M sodium
`hydroxide. A small aliquot of gastric juice was taken
`from each sample for estimation of pepsin secretion
`by the method of Berstad. 7 Results are expressed as
`mean ± standard deviation. Statistical comparisons
`were made using the Mann-Whitney U test.
`
`Results
`
`Basal and pentagastrin stimulated acid output after
`placebo were similar in the two groups. A single
`dose of 30 mg produced a 66% reduction in basal
`acid output, and a 71·2% reduction in plateau acid
`output (p<0·01) . The volume of gastric juice was
`reduced by 30·8% in the basal hour (p<0·05) and by
`47 ·1% in response to pentagastrin (p<0·01) . Basal
`pepsin secretion was not significantly altered
`although there was an apparently significant
`_(p<0·05) rise in pepsin secretion in the pentagastrin
`stimulated hour. After seven days of omeprazole 30
`mg daily, basal acid output was reduced by 99·8%
`(p<0·05) and plateau acid output by 98·4%
`(p<0·01) when compared with values following
`placebo. Five of the six subjects produced no acid in
`the basal hour and three remained achlorhydric in
`reponse to pentagastrin. The volume of gastric juice
`
`at the end of the seven day course was reduced by
`54·9% (p<0·01) and 79·2% (p<0·01) in the basal
`and pentagastrin stimulated hours respectively.
`There were no significant changes in pepsin
`secretion either basally or after pentagastrin (Table
`1).
`A single 60 mg dose of omeprazole had a much
`greater effect on acid output reducing basal acid
`output and plateau acid output by 91·7% (p<0·05)
`and 95 ·3% (p<0·01) respectively. Volumes of
`gastric juice secreta! in the basal and pentagastrin
`stimulated hours were reduced by 59·2% (p<0·01)
`and 79·5% (p<O·Ol) respectively. There was no
`significant change in pepsin secretion. After seven
`days treatment with omeprazole 60 mg daily, basal
`acid output was reduced by 99·1% (p<O·Ol) and
`plateau acid output by 99·0% (p<O·Ol). Volumes of
`gastric juice were reduced by 62·3% (p<O·Ol) in the
`basal hour and by 83·8% (p<O·Ol) in the penta(cid:173)
`gastrin stimulated hours. Pepsin secretion did not
`significantly change (Table 2).
`No side effects were encountered with
`omeprazole. Each subject kept a diary for the
`duration of the · study in which they were asked to
`note any adverse events and none was recorded.
`Subjects were also specifically asked about side
`effects on each of the three study days and, again,
`none was reported . Standard biochemical and
`haematological indices were measured before
`inclusion in the study, and were repeated within five
`days of completion of the study. No drug related
`abnormalities were found .
`
`Discussion
`
`These data show that omeprazole, in doses of 30 or
`60 mg daily, is a potent inhibitor of gastric acid
`secretion, when this is assessed around the time of
`expected maximum effect. It has no significant effect
`
`Table 1 Acid and pepsin output and volume of gastric juice after placebo, first dose of 30 mg.omeprazole and seventh dose
`of 30 mg omeprazole. (n=6; mean ± SD)
`
`Basal
`
`Acid
`output
`(mmollh)
`
`4·30
`±3·37
`1·53
`±1·91
`0·01
`±0·02'
`
`Pepsin
`output
`(mglh)
`
`22·2
`±16·4
`17·8
`±12·2
`5·2
`± 4·1
`
`Volume
`(ml)
`
`99·7
`±34·3
`69·0
`±22·6'
`45·0
`±12·0t
`
`Stimulated
`
`Acid
`output
`(mmollh)
`
`35·41
`± 5·45
`10·24
`±10·06t
`0·58
`± 0·99t
`
`Pepsin
`output
`(mglh)
`
`5·4
`± 2·9
`36·8
`±46·1'
`18·3
`±18·8
`
`Volume
`(ml)
`
`302·0
`± 42·7
`159·7
`± 66·8t
`62·7
`± 19·3t
`
`Placebo
`
`First dose
`
`Seventh dose
`
`• p<0·05.
`
`t p<0·01
`
`

`
`Effects of single and repeated doses of omeprazole on gastric acid and pepsin secretion in man
`
`709
`
`Table 2 Acid and pepsin output and volume of gastric juice after placebo, first dose of 60 mg omeprazole and seventh dose
`of60 mg omeprazole. (n=6; mean± SD)
`
`Basal
`
`Acid
`output
`(mmollh)
`
`4·56
`±3·19
`0·38
`±0·49*
`0·04
`±0·09t
`
`Pepsin
`output
`(mglh)
`
`11 ·8
`± 7·5
`13·1
`±17·1
`6·0
`± 5·2
`
`Volume
`(ml)
`
`96·3
`±25-6
`39·3
`±14·0t
`36·3
`± 8·4t
`
`Stimulated
`
`Acid
`output
`(mmollh)
`
`37·11
`±10·64
`1·74
`± 2·28t
`0·37
`± 0·20t
`
`Pepsin
`output
`(mglh)
`
`5·5
`± 6·2
`35·2
`±18·8
`24·6
`±18·5
`
`Volume
`(ml)
`
`297·3
`± 62·5
`61·0
`± 25·2t
`48·3
`± 10·2t
`
`Placebo
`
`First dose
`
`Seventh dose
`
`• p<0·05.
`
`t p<O·Ol
`
`on pepsin secretion. This is consistent with the
`proposed mechanism and site of action of the drug.
`Sixty milligrams of omeprazole produced a
`greater inhibitory effect than 30 mg after a single
`dose. This is in agreement with previous work which
`has shown a prolonged inhibition of gastric acid
`secretion which is dose-dependent. 2 After seven
`days of treatment, there was no difference between
`the two dose levels with the majority of our subjects
`being achlorhydric -
`that is, pH of gastric juice
`>7·0, in the basal hour, and the response to
`pentagastrin being inhibited by around 99%. This
`would be consistent with an increasing response with
`time as a consequence of accumulation of the effect
`of omeprazole, which for a single dose normally
`exceeds 24 hours.
`The reduction in the volume of gastric juice
`secreted after omeprazole was not of the same
`magnitude as the reduction in acid output. There
`was no concomitant reduction in pepsin secretion.
`These observations suggest that other components
`of the gastric secretion are relatively unaltered by
`omeprazole, and give further evidence for the drug's
`highly specific site and mode of action. The lack of
`reduction in pepsin secretion is unlikely to be of
`clinical importance as pepsin would be biologically
`inactive in the absence of intragastric acid.
`It is of considerable interest that the drug had no
`observed haematological, biochemical, or subjective
`side effects, despite its extremely powerful action on
`gastric acid secretion. Omeprazole has now been
`given
`to ~atients with
`the Zollinger-EIIison
`syndrome8 with good
`therapeutic effect and
`without side effects. Clearly, a degree of caution is
`necessary with any new agent, but clinical trials in
`patients with active peptic ulceration seem
`indicated. The optimum dose for ulcer healing
`remains to be found but our studies indicate that
`even 30 mg omeprazole daily produces a degree of
`
`inhibition of acid secretion in excess of that seen
`with H2 receptor antagonists. 10 11 The H2 receptor
`antagonists do not have an increasing effect with
`time.
`Although most of our subjects had basal
`achlorhydria after seven days treatment, we were
`assessing basal secretion around the time of the
`drug's maximal inhibitory effect. Other workers3
`have found degrees of acid inhibition of the order of
`30% 24 hours after a single dose, and have
`commented that the acid inhibitory effect reached a
`peak after five days treatment. It seems unlikely,
`therefore, that prolonged periods of achlorhydria
`would occur on long term treatment.
`Omeprazole is a powerful inhibitor of gastric acid
`secretion in man, and a potentially useful agent in
`peptic ulcer.
`
`This work has been presented in part to the Medical
`Research Society in January 1983 (C/in Sci 1983; 64:
`74p) and to the British Society of Gastroenterology
`in April1983 (Gut 1983; 24: A498).
`
`Capsules of omeprazole and placebo were supplied
`by Astra Pharmaceuticals.
`
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`
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`

`
`710
`
`Howden, Forrest, and Reid
`
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`·
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