33
`Omeprazole: Pharmacokinetics and Metabolism in Man
`
`C. CEDERBERG. T. ANDERSON & I. SKANBERG
`Hassle Research Laboratories, Molndal, Sweden
`
`Cederberg C, Anderson T. Skinberg I, Omeprazole: pharmacokinetics and
`metabolism in man. Scand J Gastroenterol 1989,24(suppl 166). 33-40
`Omeprazole is acid labile and, therefore, has to be protected from exposure to the
`acidic gastric juice when given orally. Following a single oral dose of buffered
`suspension. omeprazole is rapidly absorbed with peak plasma concentrations within
`0.5 hours. The volume of distribution is 0.3 litreslkg corresponding to the volume of
`extracellular water. In contrast to the long duration of antisecretory action,
`omeprazole is rapidly eliminated from plasma. The half-life is less than 1 hour, and
`omeprazole is almost entirely cleared from plasma within 3-4 hours. Omeprazole is,
`completely metabolized in the liver. The two major plasma metabolites are the
`sulphone and hydroxyomeprazole, neither of which contributes to the antisecretory
`activity. About 80% of a given dose is excreted in the urine, and the remainder via
`the bile. The absorption of the coated granule formulation dispensed in hard gelatine
`capsules is slower, with peak concentrations 1-3 hours after dose. Bioavailability
`after a single dose is 35% and increases during repeated once-daily dosing to 60%.
`Omeprazole can potentially interact with the hepatic microsomal cytochrome P-450
`enzymes. Studies show that the clearance of both diazepam and phenytoin are
`decreased and their terminal half-lives are increased during concomitant omeprazole
`treatment, both interactions being attributable to inhibition of hepatic metabolism.
`No interaction with propranolol or theophylline has been noted.
`
`Key words: Drug interactions; omeprazole; pharmacokinetics
`C. Cederberg, Gastrointestinal Clinical Pharmacology, A B Hassle, S-431 83
`Molndal, Sweden
`
`Omeprazole reduces gastric acid secretion in
`both animals and man by inhibiting the gastric
`proton (acid) pump (H+,K+-ATPase) in the
`secretory membrane of the parietal cell. The
`compound is, however, acid labile and has to be
`protected from exposure to acidic gastric juice
`when given orally. The solubility in water is very
`low. In early experimental studies in man, ome-
`prazole was, therefore, administered as an oral
`suspension in a sodium bicarbonate solution,
`together with additional bicarbonate solution
`given at the same time (1). Omeprazole has been
`given intravenously, dissolved in a 40% poly-
`ethylene glycol 400/water solution (2). This solu-
`tion, given with sodium bicarbonate to minimize
`acid degradation, has also been used for oral
`administration of
`''C-labelled
`omeprazole
`in
`many pharmacokinetic studies (3). These oral
`formulations were, however, unsuitable for clini-
`
`cal use, and omeprazole was subsequently form-
`ulated as enteric-coated granules (4). These
`granules were dispensed in ordinary hard gelatine
`capsules. This paper summarizes present know-
`ledge of the pharmacokinetics and metabolism of
`omeprazole, with special reference to the rela-
`tionship between plasma concentrations and
`effects on acid secretion.
`
`PHARMACOKINETICS OF SINGLE DOSES
`Omeprazole, given as a single oral dose in a
`buffered suspension or solution, is rapidly ab-
`sorbed and peak plasma concentrations are
`achieved within 0.5 hours ( 1 5 ) . After absorption,
`omeprazole is rapidly eliminated from the plasma
`with a terminal half-life of less than 1 hour. In
`most
`individuals, omeprazole
`is completely
`
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`
`34
`
`C. Cederberg et al.
`
`9J - w
`E 4 1
`5
`
`0 Omeprazole, 40 mg
`0 Omeprazole, 20 mg
`
`T
`
`I
`1
`
`2
`Time (hours)
`Fig. 1. Mean plasma omeprazole concentrations in 8
`healthy subjects following a single oral dose of 20 or 40
`mg as buffered suspension (data from Lind et al. (I)).
`
`cleared from the plasma within 3 4 hours (Fig. 1)
`(1). Studies with oral administration of 14C-
`labelled omeprazole have shown that there is
`rapid and extensive formation of plasma meta-
`bolites (Fig. 2) (5). The plasma concentration-
`time curve for both omeprazole and the total pool
`of metabolites declined quickly indicating rapid
`elimination from the body; this is in contrast to
`
`0 Total metabolite pool
`0 Omeprazole
`
`5 2.0
`
`-2.5
`2
`
`-
`.- - .
`1
`5
`.- -
`8 1.5
`e
`5 1.0
`8 2 0.5
`a
`B
`
`4-
`
`c
`
`0
`
`1
`
`2
`
`3
`4
`Time (hours)
`Fig. 2. Median plasma concentration-time curves for
`omeprazole and the total pool of radioactive metabolites
`in six healthy subjects following a single oral dose of
`''C-labelled omeprazole as a buffered solution (data
`from Reglrdh et al. (3)).
`the long duration of antisecretory action, which
`lasts for 3-4 days after a single dose (Fig. 3) (1,3).
`Thus, the degree of acid inhibition at any given
`time is independent of the plasma concentration
`of omeprazole or any of its metabolites. However,
`a significant correlation has been found between
`the degree of acid inhibition 2-4 hours after an
`oral dose and the area under
`the plasma
`
`A Percentage inhibition of stimulated
`acid secretion
`0 Metabolites
`0 Omeprazole
`
`0
`
`20
`
`80
`Time (hours)
`Fig. 3. Mean percentage inhibition of pentagastrin-induced acid secretion in six healthy subjects at various time
`points following a single oral dose of omeprazole, 20 mg, as buffered suspension (data from Lind er al. (1)) and
`median plasma concentration-time curves for omeprazole and the total pool of radioactive metabolites in six other
`healthy subjects following a single oral dose of ''C-labelled omeprazole as a buffered solution (data from Reglrdh
`et al. (3)).
`
`40
`
`60
`
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`
`Omeprazole: Pharmacokinetics and Metabolism in Man
`
`35
`
`loo 1
`
`40
`
`20
`
`a
`
`I
`I
`0.1
`10
`1
`Plasma omeprazole AUC (pmol x hoursllitre)
`Fig. 4. Correlation between individual values for the
`area under the plasma omeprazole concentration-time
`curve (AUC) and percentage inhibition of pentagastrin-
`induced acid secretion 2 4 hours after various single oral
`doses of omeprazole buffered suspension in healthy
`subjects. Reproduced with permission from Lind et al. (1).
`
`omeprazole concentration-time curve (AUC)
`(Fig. 4) (1). The omeprazole A U C reflects the
`product of the concentration of omeprazole in
`plasma and the time it is available in the sys-
`temic circulation and, therefore, available to the
`parietal cells.
`Omeprazole is a lipophilic weak base. It is
`distributed into the parietal cells when available
`in the systemic circulation. Within the parietal
`cells omeprazole is concentrated in the acidic
`compartments because it is a weak base (6). In
`this acidic environment, omeprazole is proton-
`ated and chemically transformed to its active
`sulfenamide form, which binds and inactivates the
`proton transporting ATPase in the secretory
`membrane (6). The long-lasting binding of the
`active form of omeprazole to the H+,K+-ATPase
`in the parietal cells accounts for the lack of cor-
`relation between plasma concentration and
`degree of acid inhibition at any given time (6).
`Thus, the initial degree of acid reduction is
`dependent on the amount of drug available to the
`parietal cells, but the duration of acid inhibition
`is not dependent on sustained plasma concen-
`trations.
`
`METABOLISM AND ELIMINATION
`After single oral and intravenous doses of I4C-
`labelled omeprazole in young healthy subjects,
`
`about 80% of the radioactivity was detected in the
`urine and the remainder in the faeces (5). The
`amount recovered was similar for both routes of
`administration. No unchanged omeprazole was
`found in either the urine or the faeces. This
`suggests that omeprazole is completely meta-
`bolized before excretion. The bioavailability of
`the oral dose was about SO%, which indicates a
`fairly extensive first-pass metabolism.
`The two main plasma metabolites in man have
`been identified as the sulphone and hydroxy-
`omeprazole (Fig. 5) (5). The sulphone does not
`possess any antisecretory activity and hydroxy-
`omeprazole is more than 100 times less potent
`than omeprazole (Wallmark B, personal com-
`is
`munication).
`Some
`hydroxyomeprazole
`excreted in the urine, but a fraction is probably
`further metabolized to the corresponding car-
`boxylic acid, which has been identified in the
`urine (5). The sulphone, on the other hand, isonly
`found in very small quantities in the urine and
`most seems to be further metabolized to more
`polar metabolites (5).
`The biliary excretion of omeprazole has also
`been studied using intravenous administration of
`a very small (non-antisecretory) dose of radio-
`labelled omeprazole (7). During the first 4 hours,
`16% of the given dose was recovered in the bile.
`As omeprazole is a weak base and, therefore,
`could be excreted via the acidic gastric juice, this
`route of excretion was also studied. However,
`negligible amounts (4%) of the given dose were
`found in the gastric juice during the first 4 hours.
`It was concluded that the faecal recovery of
`omeprazole metabolites can be solely explained
`by biliary excretion and that this is the only
`important gastrointestinal route of elimination.
`
`COMPARATIVE PHARMACOKINETICS
`The pharmacokinetics of single oral and intra-
`venous doses of radiolabelled omeprazole have
`been studied in different categories of patients
`(5,s). The mean plasma omeprazole concen-
`tration-time curves are shown in Fig. 6 and the
`pharmacokinetic variables summarized in Table I.
`In patients with impaired renal function, the
`kinetics of unchanged omeprazole were essen-
`
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`

`
`36
`
`C. Cederberg et al.
`
`Omeprazole acid Hydroxy-
`omeprazole
`- C H , O H t H3C
`
`-COOH*--.
`
`?CH3
`
`Fig. 5 . Major metabolic pathways of omeprazole in man.
`
`CH2-
`
`S
`
`I
`
`H
`
`1
`- ’- sulphone
`II
`
`Omeprazole
`
`0
`
`0
`
`0 Impaired hepatic function
`0 Elderly healthy subjects
`Impaired renal function
`A Healthy subjects
`
`C .- * E
`C 8 2
`8
`
`4-
`
`0
`
`**o......
`...
`‘0 .... , . . .
`-0.. . . . . .
`“O.... .
`”‘0-.. ..... . ......
`I T -
`..o ...................
`0
`9
`12
`Time (hours)
`Fig. 6. Mean plasma concentration-time curves for omeprazole after a single oral dose of 40 mg, as a buffered
`solution in 18 young healthy subjects (3), 14 elderly healthy subjects (5), 12 patients with various degrees of renal
`function impairment (8), and 6 patients with various degrees of liver function impairment.
`
`-m-..-..-..+
`f
`A
`
`. . -.
`
`- -..
`
`8
`
`tially similar to those in healthy subjects. The rate
`of elimination of the total pool of metabolites was
`slower in these patients but, despite a marked
`reduction in kidney function, the elimination rate
`for the total pool of metabolites was such that no
`major accumulation is expected to occur during
`
`once-daily dosing (8). In elderly patients, the rate
`of elimination of omeprazole was on average
`slower and the bioavailability somewhat greater,
`while in patients with impaired hepatic function,
`the metabolism was considerably slower and the
`bioavailability close to 100%. It must be pointed
`
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`
`Omeprazole: Pharmacokinetics and Metabolism in Man
`
`37
`
`Table I. Pharmacokinetic variables for a single oral dose of omeprazole, 40 mg, in buffered solution and a single
`intravenous dose of omeprazole, 20 mg. Values are given as median with range. From the data referred to in Fig. 6
`
`Young healthy subjects,
`n=18 (3)
`Elderly healthy subjects,
`n=14 ( 5 )
`Patients with impaired
`hepatic function. n=8 (5)
`Patients with impaired
`renal function. n= 12 (8)
`
`Clearance
`(litres/minute)
`
`0.62
`(0.064.83)
`0.23
`(0.08-0.48)
`0.07
`(0.04-0.08)
`0.54
`(0.27-0.93)
`
`Half-life
`(hours)
`
`0.50
`(0.27-2.52)
`0.84
`(0.49-2 .OO)
`2.68
`(2.09-3.52)
`0.48
`(0.34-0.93)
`
`VP
`(litreslkg)
`
`0.32
`(0.18-0.55)
`0.23
`(0.22-0.34)
`0.20
`(0.19-0.26)
`0.34
`(0.27-0.48)
`
`F
`
`0.46
`(0.25-1.17)
`0.79
`(0.33-1.14)
`0.98
`(0.82-1.13)
`0.71
`(0.10-1.24)
`
`2 30
`c
`X
`
`0
`
`0
`
`0
`
`0
`0 .
`
`0
`0
`
`0
`
`0 .
`
`Young
`
`Elderly
`
`v
`
`Impaired hepatic
`Impaired renal
`function
`function
`Fig. 7. Individual data for the area under the plasma omeprazole concentration-time curve (AUC) following a
`single oral dose of omeprazole, 40 mg, as a buffered solution. From the data referred to in Fig. 6.
`
`out that the half-life of omeprazole in these
`patients was still as short as 2-4 hours. This
`suggests that the degree of general liver function
`impairment does not necessarily parallel the
`change in omeprazole metabolism, particularly
`as some young healthy subjects had similar half-
`lives and plasma AUCs (Fig. 7).
`The most important pharmacokinetic variable
`antisecretory effect of
`for
`the degree of
`omeprazole seems to be the plasma concen-
`tration AUC with which it has a close relationship.
`
`The range of individual data for the omeprazole
`AUC (Fig. 7) in most subjects was similar in
`healthy subjects and patients with impaired renal
`function. In elderly patients, the AUC was on
`average higher, but there was a considerable
`overlap with the last two categories. Patients
`with impaired hepatic function had a consistently
`higher AUC than normal subjects.
`Two healthy subjects had much higher AUC
`values than others in their group. Their AUC
`values were in the same range as those found in
`
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`

`
`38
`
`C. Cederberg er al.
`
`patients with impaired liver function. These STUDIES WITH OMEPRAZOLE ENTERIC-
`variations in omeprazole metabolism in normal COATED GRANULES
`young subjects may possibly be due to genetic For clinical use, omeprazole is formulated as
`differences in drug metabolism, as has been
`enteric-coated granules (4) which are dispensed
`described for other drugs (9). However, further
`in hard gelatine capsules. The absorption from
`studies are needed to clarify this.
`this formulation was slower than that from a
`buffered solution o r suspension. Peak plasma
`concentrations generally occurred 1-3 hours
`after the dose and the plasma concentration pro-
`file was, therefore, flatter and more extended in
`time (Fig. 8). The bioavailability was 35% after a
`single dose. Several studies have shown in-
`creased plasma omeprazole concentrations
`during once-daily dosing with the enteric-coated
`formulation in doses of 20-60 mg (17, 18). The
`bioavailability, as assessed by a simultaneous
`injection of a
`''C-labelled
`tracer dose of
`omeprazole, was increased to about 60% after 7
`days' administration (data on file, AB Hassle).
`
`DRUG INTERACTIONS
`As omeprazole is extensively metabolized by the
`liver, presumably via the cytochrome P-450
`system, interactions with other drugs also under-
`going hepatic metabolism may occur.
`In addition, omeprazole is a benzimidazole
`derivative and many imidazoles and benzimida-
`zoles are known to inhibit hepatic microsomal
`oxidation (10). Therefore, several studies to
`determine possible interactions with other drugs
`have been performed (11-16). Concomitant
`omeprazole administration significantly inhibited
`the hepatic metabolism of phenytoin (11,13),
`diazepam (1 l), R-warfarin (15), aminopyrine (16)
`and antipyrine (16), but not of theophylline (15),
`S-warfarin (15) or propranolol (14). These
`changes were interpreted as an inhibition of the
`hepatic metabolism of these drugs.
`The main results from these studies with
`omeprazole are summarized in Table 11. The
`interaction with diazepam is unlikely to be of
`clinical significance. However, the elimination of
`phenytoin and warfarin is prolonged, and, in some
`patients, this may be clinically significant. Thus,
`monitoring of patients receiving these drugs con-
`comitantly with omeprazole is recommended and
`a reduction in their dose may be necessary.
`
`
`
`0 Suspension
`0 Enteric-coated
`granules
`
`5
`0 E
`0 - 4
`L
`.s 7 3
`G i 2
`2z Z E 2
`g 3 1
`8
`-
`m g
`o
`1
`6
`a
`Time (hours)
`Fig. 8. Mean plasma concentration-time curves
`following a single oral dose of omeprazole, 60 mg, as
`buffered suspension or enteric-coated (EC) granules in
`six healthy subjects. Reproduced with permission from
`Pilbrant and Cederberg (4).
`
`
`
`1
`
`2
`
`3
`
`4
`
`5
`
`
`
`Table 11. Effect of once-daily omeprazole, 20 mg, on the kinetics of concomitant drugs
`
`Drug
`
`Route Dose
`
`Effect
`
`Source of data
`
`Phenytoin
`Diazepam
`Warfarin
`
`i.v.
`i.v.
`p.0.
`
`Theophylline $ i.v.
`Propranolol
`p.0.
`
`Gugler & Jensen (11)
`Clearance decreased by 20%
`250 mg*
`(Unpublished data)
`Clearance decreased by 27%
`0.1 mg/kg*
`4.7 mg o.mt R-warfarin concentration increased by 12% Sutfin et al. (15)
`S-warfarin concentration unchanged
`Coagulation time increased by 11%
`No significant change
`No significant change
`
`Gugler & Jensen (14)
`Henry et al. (12)
`
`2.5 mg*
`80 mg b.d.t
`
`'Single dose; tRepeated dosing; *Omeprazole, 40 mg.
`
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`
`Omeprazole: Pharmacokinetics and Metabolism in Man
`
`39
`
`The reason for this change is not fully understood,
`but may be due to decreased first-pass metabolism.
`However, increased absorption, due to the
`marked decrease in intragastric acidity obtained
`during treatment, may be contributory (18).
`Several studies of both pentagastrin-induced
`gastric acid secretion
`(19,20) and 24-hour
`intragastric acidity (18, data on file, AB Hassle),
`during once-daily dosing with the enteric-coated
`formulation of omeprazole, have shown that the
`degree of acid inhibition increased during the first
`few days of administration. This
`increased
`pharmacological effect was, in most cases, asso-
`ciated with
`increased plasma concentrations.
`The increased acid inhibitory effect is, however,
`not only due to increased plasma concentrations,
`because a similar increase was seen in studies
`using
`repeated
`once-daily
`dosing with
`omeprazole, 10 mg intravenously, but in which
`plasma concentrations were unchanged (unpub-
`lished data). This latter increase can be explained
`by the long duration of the antisecretory action
`of omeprazole leading to an increase in the
`number of inhibited enzyme molecules during
`once-daily dosing. This effect does, however,
`seem to stabilize after 3-4 days (19), after which
`no further increase takes place (21).
`The absorption from the enteric-coated for-
`mulation was not influenced by simultaneous
`food intake (22) or concomitant dosing with a
`high capacity antacid preparation (23).
`
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`Page 8 of 8
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`Patent Owner Ex. 2004
`Lupin v. Pozen
`IPR2015-01774