Gut, 1984, 25, 70';'+'i'10
`
`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 Mareria Median 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-?% 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+iK+-ATPase
`enzyme on the secretory membrane of the parietal cell. There were no side effects after
`omeprazole either with single or repeated dosing.
`
`(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
`
`The substituted benzimidazoles are new agents
`which are potent inhibitors of gastric acid secretion.
`They act by selective, non-competitive inhibition of
`the H+!'K+-ATPEISB enzyme in the parietal cell.‘
`This enzyme is the active transport mechanism for
`Glasgow Health Board, Northern District.
`hydrogen ion secretion in the stomach. Although
`t
`one of tl't€I"‘
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`s--note“ haw‘ =md..pprU.a."=Ist.tin. slim-ilatedcgariti... rsro-.rur....Ear‘l2.rexeivgrtops. 2...-.. ."....'......'.. .,I..3'do
`after three to five days by cit
`secretion after a single dose? little is known about
`its effects after
`repeated dosing.
`In addition,
`omeprazole orally as a sing]
`previous studies have used a buffered suspension of
`clays. Subjects attended the I
`Research Laboratory on thre
`the drug2 as it is partially inactivated by gastric acid,
`or have looked at its acid inhibitory effect 24 hours
`study: day 0 (placebo); day 0
`after a dose.3
`zole} and day seven {seventh a
`We have studied the effects of two different doses
`study design was
`identical
`Subjects arrived -fasted at at
`were given capsules cont
`omeprazole granules or plac
`breakfast was given 15 minu
`stration and the subject re I
`remainder of the study day.
`(or 53 hours postdose) a siz
`gastric tube was passed and i
`means of a water recovery t
`until 1530 hours — that is, fr
`postdose — gastric juice was .
`and collected as
`four
`15
`measurement of basal acid 0
`hour. each subject received a
`of pentagastrin (1-2 p.gil-tg.*'h}
`707
`
`U
`
`e'ot placebo tollowed
`er 30 mg or 60 mg of
`daily dose for seven
`linical Pharmacology
`' occasions during the
`e (first dose omepra-
`ose omeprazole). The
`on each occasion.
`und 0830 hours and
`
`ining enteric-coated
`be. A standard light
`cs after drug admini-
`ained fasted for the
`I around 1415 hours
`16 FG vented naso-
`s position checked by
`chniquc.‘ From 1430
`m six to seven hours
`spirated continuously
`minute samples for
`tput. During the next
`intravenous infusion
`and gastric juice was
`
`of omeprazole on basal and pentagastrin stimulated
`acid and pepsin secretion after a single dose and
`after seven days of treatment. Capsules of enteric-
`coated omeprazole granules were used. and the
`effects studied around the time of expected
`maximum acid inhibition.
`
`Methods
`
`SUBJECTS
`
`Twelve healthy male subjects, mean age 25-2 years
`
`Address for correspondence: Dr C W Howdcn. Department of Materia
`Medics. Slobhill General I-tospila1.Glasgnw G21 3L.IW. Scotland.
`Received for publication 29 July 1933
`
`Lupin Exh. 1006
`
`

`
`708
`
`Hon-den, Forrest, and Reid
`
`15
`continuously aspirated and collected as four
`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.‘ 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 i 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-C0-01) 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 91-73% (p<0-05)
`and 95-3% (p-<0-01)
`respectively. Volumes of
`gastric juice secretal in the basal and pentagastrin
`stimulated hours were reduced by 59-29% (p<0-01)
`and 79-5% (p<0-01) 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-<0-01) and
`plateau acid output by 99-0% (p<0-01). Volumes of
`gastric juice were reduced by 62-3% (p<0-01) in the
`basal hour and by 83-8% (p<0-01) in the penta-
`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 ofgastrtcjuice after placebo. first dose of30 mgomeprazoie and seventh dose
`of 30 mg omepntzote. (t‘l=6,' mean : SD)
`Basal
`Stimulated
`
`Acid
`Pepsi}:
`Acid
`output
`output
`output
`
`
`(mt)(mgfhllmmolflil (mmoltlrl
`
`
`
`22-2
`1&3!)
`116-4
`:33?
`173
`1'53
`:12-2
`ii-91
`62-7
`5-2
`0-01
`Seventh dose
`I3‘-3
`i 1931'
`1 4-1
`ifl-02'
`__m—
`
`'
`
`54
`
`Placebo
`
`First dose
`
`‘ p-<0-0'5.
`
`1' p<.{)‘Ul
`
`

`
`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 ofgastric juice afiter placebo, firs: dose of 60 mg omeprazole and seventh dose
`of 60 mg omeprazole. (n=6; mean 1 SD)
`
`Pepsin
`output
`
`Basal
`
`Acid
`output
`(mmaith)
`
`4-56
`:3-19
`0-3
`$049"
`0434
`10-091'
`
`Placebo
`
`First dose
`
`Seventh dose
`
`- p<o-us.
`
`+ 1340-01
`
`Stimulated
`
`Acid
`output
`(mmolth)
`
`37-] l
`1 10-64
`I -74
`‘J: 2'28?
`0-3?
`‘L Uviflf
`
`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} 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 patients with the Zollinger-Ellison
`syndrome“ 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.” ” The H2 receptor
`antagonists do not have an increasing effect with
`time.
`
`subjects had basal
`Although most of our
`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 (Clin Sci 1983; 64:
`74p) and to the British Society of Gastroenterology
`in April 1983 (Out 1983; 24: A498).
`
`Capsules of omeprazole and placebo were supplied
`by Astra Pharmaceuticals.
`
`References
`
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`

`
`710
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`Howden, Forrest, and Reid
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