GASTROENTEROLOGY 1985;88:64-9
`
`Omeprazole: A Study of Its Inhi~itio:n of
`Gastric pH and Oral Pharmacokinetics
`After Morning or Evening Dosage
`
`PETER J. PRICHARD, NEVILLE D. YEOMANS ,
`GEORGE W. MIHALY, D. BRIAN JONES, PETER J. BUCKLE,
`RICHARD A. SMALLWOOD, and WILLIAM J. LOUIS
`Departments of Gastroenterology and Clinica l Pharmacologyffherapeutics, Division of Medicine,
`University of Melbourne, Austin Hospital, Heidelberg, Victoria , Australia and Astra
`Pharmaceuticals, North Ryde 2113 , New South Wales, Australia
`
`Pharmacodynami c and pharmacokineti c studies of
`omeprazole , a new gastric antisecretory agent, were
`undertaken in 8 healthy subjects. Th e drug was
`administered orally as an encapsulated enteric(cid:173)
`coated granulate (40 mg daily at 9 AM or 9 PM for 5
`days), and its effect on the integrated 24-h gastric pH
`was determined, together with its apparent bioavail(cid:173)
`ability. The pretreatm ent 24-h median pH was 1.9
`(interquartile range 1.4-2.9 ). After 5 days of trea t(cid:173)
`ment, the m edian pH had risen to 5.0 (3.7-6.0) (p <
`0.01) with morning dosage and 4.5 (3.0-5.6) (p <
`0.01) with evening dosage. This corresponded to a
`> 99% reduction in 24-h median hydrogen ion activ(cid:173)
`ity, with morning dosage having a greater effect
`(from 9 AM to 8 PM) (p < 0.01) than evening dosage.
`The relative bioavailability of omeprazole increased
`twofold from day 1 to day 5 of treatment with
`morning dosage (p < 0.02) and threefold with eve(cid:173)
`ning dosage (p < 0.02) , suggesting that increased
`absorption of this acid-labile drug occurs with in(cid:173)
`creasing inhibition of acid secretion. We con clud e
`that this formulation of omeprazole presentl y being
`used in clinical trials is a highly potent antisecretory
`
`Received jan uary 23, 1984. Accepted jul y 16 , 1984.
`Address requests for reprints to: Neville D. Yeomans, M.D.,
`Gastroenterology Unit, Department of Medicine , Austin Hosp ital.
`Heidelberg 3084 , Victoria , Australia.
`This work was supported by the Nat ional Hea lth and Medical
`Research Council of Australia.
`A preliminary communication of part of this work has appea red
`as an abstract (1) and was presented at th() Annual Scientific
`Meeting of the Gastroenterological Society of Austra lia, Perth ,
`Australia , May 1983.
`The authors thank Or. john McNeil for help with computer
`processing.
`© 1985 by the American Gastroenterological Association
`0016-5085/85/$3.30
`
`agent in humans, although its optimal effect may not
`be observed for several days.
`
`Omeprazole, a substituted benzimidazole, is a potent
`long-acting inhibitor of gastric acid secretion (2).
`Omeprazole has been shown to act by inhibition of
`H+ ,K+ -adenosine triphosphatase, a proton pump
`that seems to be peculiar to the gastric parietal cell
`(3- 7). The initial clinical studies of omeprazole
`appear promising in that the drug has been shown to
`promote duodenal ulcer healing (8 ,9), and to control
`Zollinger-Ellison syndrome symptoms when other
`drugs have failed (10-12). To date there is little
`information about the antisecretory activity of ome(cid:173)
`prazole in humans (2,13,14), and human pharmaco(cid:173)
`kinetic data of this drug are restricted to those
`obtained using a single dose of a buffered suspension
`or an encapsulated uncoated granulate given with
`liquid buffer (2 ,14). As omeprazole is acid-labile,
`unprotected exposure to acidic gastric contents re(cid:173)
`sults in inactivation of > 50% of an oral dose (Skan(cid:173)
`berg I, personal communication) . Thus the formula(cid:173)
`tion of the oral preparation will have a profound
`effect on the pharmacokinetics, and on the antisecre(cid:173)
`tory effect of the drug.
`In the present study we have examined the oral
`pharmacokinetics and the gastric antisecretory activ(cid:173)
`ity of omeprazole formulated as an encapsulated,
`enteric-coated granulate, which is the form currently
`undergoing clinical trial (8) . Two particular ques(cid:173)
`tions have been considered: (a) whether morning or
`evening administration of a daily 40-mg dose gives
`better control of 24-h intragastric pH, and (b) wheth(cid:173)
`er the oral bioavailability of this formulation in(cid:173)
`creases during the initial phase of treatment as acid
`secretion declines.
`
`

`
`January 1985
`
`OMEPRAZOLE: DYNAMICS AND KINETICS 65
`
`Material and Methods
`Subjects
`Eight healthy male volunteers were studied. Mean
`age was 22 yr (range 20-26 yr), and mean weight was 74 kg
`(range 63-116 kg) . None were smokers, and none had a
`history of peptic ulcer dis(lase. Physical examination,
`electrocardiogram, and laboratory scr·een were normal
`before inclusion.
`Informed written consent was given by all subjects, and
`the study was approved by the Human Experimentation
`Committee of the University of Melbourne on November
`24, 1982.
`
`Drug
`
`Omeprazole is a crystalline solid that is chemically
`labile and rapidly degraded in acidic media. It was there(cid:173)
`fore administered as an encapsulated, enteric-coated gran(cid:173)
`ulate (each capsule containing 20 mg of omeprazole) . Drug
`and matching placebo capsules were provided by Astra
`Pharmaceuticals (North Ryde, Australia).
`
`Study Design
`
`Patients were admitted to a special hospital ward
`on five occasions for 24-h gastric pH or pharmatokinetic
`studies, or both. Meals and fluid intake were identical
`during each study day. Small meals and snacks were given
`at 8 AM, 11 AM, 4 PM, and 11 PM, and main meals were given
`at 12 noon and 6 PM. The patients were not confined to
`bed, but maintained normal daily activity within the
`confines of the study area.
`Subjects first underwent a baseline study of gastric pH
`(day 0), during which placebo capsules were given at 9 AM
`and 9 PM. Thereafter, the subjects were randomly assigned
`to one of two treatment groups. The first group initially
`received omeprazole ( 40 mg) at 9 AM and placebo at 9 PM.
`The second received placebo at 9 AM and omeprazole at
`9 PM. Each group took their medication at the specified
`times for 5 days (period 1), followed by a 15-day washout
`period when no medication was administered. The sub(cid:173)
`jects were then crossed over to the alternative dosage
`schedule for a further 5 days of medication (period 2).
`Food was withheld for 1 h before and 2 h after capsule
`administration. On day 1 of each period, subjects under(cid:173)
`went a pharmacokinetic study. On day 5 of each period,
`they were again studied in the hospital , with measurement
`of both pharmacokinetics and gastric pH. During the
`intervening days at home the subjects continued to eat
`meals at similar times to those during the hospital study
`days.
`
`Gastric pH Studies
`
`Each subject was intubated at 7 AM with a 1DF
`nasogastric Salem sump tube (Argyle, St. Louis , Mo.),
`which was positioned, under fluoroscopic control, in the
`most dependent part of the stomach. Samples (2 ml) of
`gastric juice were aspirated hourly throughout the day
`from 8 AM until 9 AM on the following day. The pH of each
`
`sample was immediately determined using a glass elec(cid:173)
`trode and digital pH meter (Orion Research model 611 ,
`Orion Research Inc., Cambridge, Mass.). The pH meter was
`caiibrated with Merck standard buffers (E. Merck, Darm(cid:173)
`stadt, West Germany) at pH 2.0 and pH 7.0, and linearity of
`the slope was verified at pH 4.0. The calibration was
`checked at regular intervals and varied by < 0.1 pH units
`during the course of the day. Hydrogen ion activity was
`calculated by direct conversion of pH to millimoles per
`liter of free hydrogen ions .
`
`Pharmacokinetic Studies
`
`Each subject had an intravenous cannula inserted
`into a forearm vein at 7:15 AM. Five milliliters of blood was
`collected into a heparinized tube, before the omeprazole or
`placebo dose, and at 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6,
`6.5, 7, 8, 10, and 12 h postdose. Samples we're immediately
`centrifuged for 5 min and the plasma was transferred to
`plastic tubes containing 10 ~-tl of 1 M Na 2C0 3 . Urine
`samples were alsq collected predose, and for the period 0-
`12 h postdose. At the end of each collection period, urine
`pH and volume were determined , and a 5-ml aliquot was
`added to a plastic tube containing 20 ~-tl of 1 M Na 2C03 • All
`samples of plasma and urine were stored at - 20°C.
`
`Drug Assays and Pharmacokinetic
`Calculations
`
`Plasma and urine samples were assayed for ome(cid:173)
`prazole and for two of its metabolites, omeprazole sulfone
`and omeprazole sulfide, using a high pressure liquid
`chromatographic method (15) . Sensitivities were 5, 30,
`and 50 ng/ml for omeprazole, omeprazole sulfone, and
`omeprazole sulfide, respectively. The corresponding coef(cid:173)
`ficients of variation were 4%, 7%, and 17%.
`Areas under the plasma concentration-time curve from
`time 0 to either the last detectable plasma level (Cd or 12 h
`(Ct=CJZ) (AUC0 • 1) were determined using the linear trape(cid:173)
`zoidal rule (16). In all studies plasma levels of omeprazole
`were undetectable at time zero, so that there was no need
`to correct for residual drug in the AUC calculations after
`repeated dosage. The ratios of AUC0 . 1 on day 5 to that on
`day 1 were taken as a measure of relative bioavailability
`(16). Peak concentration (Cpk) and time to peak concentra(cid:173)
`tion (Tpk) were calculated directly from the plasma con(cid:173)
`centration data for each individual. Apparent elimination
`half-life (t1121l) was calculated where possible by regression
`of the log-linear portion of the plasma elimination phase.
`
`Safety Evaluation
`
`On each hospital study day, pulse rate , blood
`pressure, and electrocardiogram were monitored at fre(cid:173)
`quent intervals, and patients were questioned about ad(cid:173)
`verse symptoms. A laboratory screen that included plasma
`urea and electrolytes, hepatic enzymes, thyroid function
`tests, hemoglobin, hematocrit, differential white cell
`count, platelet count, and urinary analysis was performed
`before the baseline day, and 7 and 28 days after the last
`omeprazole dose.
`
`

`
`66 PRICHARD ET AL.
`
`GASTROENTEROLOGY Vol. 88 , No. 1, Part 1
`
`Statisti cal Analysis
`
`Because of significant skewness (17) of the di stri(cid:173)
`butions of pH and h ydrogen ion activity, these data have
`been presented not as means and standard errors but as
`medians ~ith interqu artile ranges . The median was a more
`representative measure of central location , or in other
`words of "average value," than either the ordinary arith(cid:173)
`meti c mean or the geometric mean (arithmetic mean of log(cid:173)
`transformed data). Other data that were normall y distribut(cid:173)
`ed are presented , as usual , as mean ± SEM. Gastric pH and
`hydrogen ion activity were compared using distribution(cid:173)
`independent nonparametri c methods (Wilcoxon's signed(cid:173)
`ranks test) (17) . Before applying these m ethods, the hourly
`data of a subject were summarized into one value (median)
`for the time period being evaluated (18) . Determination of
`significant differences in other data was made using paired
`Student 's t-tests (17). A value of p < 0.05 was regarded as
`significant.
`
`Results
`Gastric Acidity Studies
`
`The patterns bf gastric pH over 24 h , before
`and on day 5 of treatment with omeprazole, taken
`either in the morning or evening, are shown in
`Figure 1. The gastric pH throughout the 24 h was
`substantially higher with both regimens of active
`omeprazole administration than on the control day
`("p < 0.01, Wilcoxon's signed-ranks test). The median
`pH's over this period were 5.0 and 4.5 for morning
`and evening dosage , respectively, and 1.9 for the
`control study.
`When the pH-time profiles were divided into two
`12-h periods, the median pH after morning dosage of
`orheprazole was 5.4 in the period from 9 AM to 8 PM
`and 4.5 from 9 PM to 8 AM. After evening dosage, the
`
`:z:
`a.
`
`" . .. Cl
`
`corresponding median pH's were both 4.3. Thus,
`morning dosage resulted in a higher gastric pH
`during the period from 9 AM to 8 PM (p < 0.01 ,
`Wilcoxon's signed-ranks test) , but from 9 PM to 8 AM
`the control of gastric pH was similar with both
`morning arid evening administration of omeprazole.
`One measure of the usefu lness of gastric antisecre(cid:173)
`tory drugs is the proportion of the day during which
`the pH of gastric juice is kept above the activity range
`of pepsin (i.e. , to pH 2: 5.0) . During the control
`study, the gastric pH was 2: 5.0 in only 3% of
`determinations (taken !:!very 60 min), in contrast to
`51% with morning and 34% with evening dosage
`administration.
`When pH values were converted to hydrogen ion
`activities, the 24-h medians during day 5 of omepra(cid:173)
`zole treatment were 0.01 and 0.04 mmol!L for morn(cid:173)
`ing and evening dosage , respectively, compared with
`12.6 inmol!L for the control study. For both omepra(cid:173)
`zole regimens this represents inhibition of hydrogen
`ion activity of > 99%.
`The principal g~stric pH and hydrogen ion activity
`data are summarized in Table 1. The highly signifi(cid:173)
`cant skewness values and the large differences be(cid:173)
`tween variances of the individual groups [Bartlett's
`test, pH data: x2 = 20.6 (p < 0.001); hydrogen ion
`activity: ;.( 2 = 744.1 (p < 0.001)] indicate that the
`data are not normally distributed and are, therefore,
`not appropriately expressed as mean ± SD. Howev(cid:173)
`er, to allow comparison with other studies (13 ,19)
`the arithmetic mean has been included in Table 1.
`
`Pharmacokinetic Studi es
`
`The mean plasma concentration-versus-time
`profiles for omeprazole on days 1 and 5 after morn(cid:173)
`ing and evening dosage are shown in Figure 2.
`Pharmacokinetic parameters for omeprazole and one
`of its metabolites, omeprazole sulfone, are summa(cid:173)
`rized in Table 2. The second metabolite, omeprazole
`
`Tabl e 1. Gastric pH and H + Activity, Medians, and
`Other Population Parameters for the 24-Hour
`Peri od
`
`Median
`
`Interquartile Arithmetic
`mean ± SO Skewness
`range
`
`1.9
`5.0
`4 .5
`
`1.4-2.9
`3.7-6.0
`3.0-5.6
`
`2.3 ± 1.2
`4.8 ± 1 .4
`4.4 ± 1.7
`
`1.22"
`- 0.41 b
`- 0.08
`
`12.6
`0.01
`0.04
`
`1.3-39.8 26.1 ± 32 .9
`1 .1 ± 3.3
`0.001-0.2
`3.7 ± 10.3
`0 .003-1.0
`
`1.47"
`4.24"
`3.86"
`
`pH
`Baseline
`Morning dose
`Evening dose
`H+ activity
`(mm ol!h)
`Baseline
`Morning dose
`Evening dose
`
`0 p < 0.001. b p < 0.025.
`
`0900
`
`~-·-.-----*-.-*----~--*---.-----.-----*,
`osoo
`
`0900
`
`!300
`
`1700
`
`2100
`
`0100
`
`Time
`( houro)
`Figure 1. Gastric pH-ti me profi les for the base line study (open
`triangles) and after 5 days of omeprazole administra(cid:173)
`ti on in the morning (closed circles) or even ing (open
`circles). Va lu es are medians with interquartile ranges
`(n = 8). Closed triangles, dosage times (omeprazole
`or placebo); closed stars, main meals: open stars. srna ll
`meals an d snacks.
`
`

`
`january 1985
`
`OMEPRAZOLE : DY NAMICS A D KI NETICS 67
`
`AM Dosage
`
`Dosage
`
`Day 1
`
`5000
`
`100"[
`
`~
`
`0 l ..
`
`0
`
`12
`
`(hOUtl)
`
`Time
`Figure 2. Pl as ma concentrati on-time curves for ome prazole (40
`mg) on da y 1 and day 5 of dosage. given AM or P M .
`Va lues a re th e mean con centrati on with SEM (n = 8).
`
`Time
`
`(hours)
`
`sulfide, was infrequently detected in plasma, and
`was not subjected to pharmacokinetic analysis.
`Between day 1 and day 5 of omeprazole dosage,
`given either in the morning or the evening, there was
`a significant increase in the area under the omepra(cid:173)
`zole plasma concentration-time curve (AUC0 _r) (p <
`0.02) , and also in the peak plasma concentration
`achieved (p < 0.05) . This increase in AUC over 5
`days , which occurred in every subject (Figure 3),
`represents a 1.9-fold increase in relative bioavailabil(cid:173)
`ity with morning dosage and a 2.9-fold increase with
`evening dosage .
`On day 1 of therapy the time to peak plasma
`concentration was shorter (p < 0.02), peak concen(cid:173)
`tration was higher (p < 0.01) , and AUC was greater
`(p < 0.05) with morning dosage. On day 5, however,
`the differences in these parameters between morning
`and evening dosage were no longer statistically sig(cid:173)
`nificant.
`Elimination half-lives (t 112f:l) of omepazole could
`not be characterized in eight of thirty-two plasma
`concentration profiles because of erratic and contin-
`
`~ 3000
`..:
`ai c::
`
`u
`::I c
`
`2000
`
`1000
`
`~:ft
`t :y
`
`t
`~~
`
`l
`
`t
`
`0
`STUDY DAY:
`
`5
`
`5
`
`A-M.
`DOSE TIME :
`Figure 3. Area under the om eprazole plasma concentra tion-time
`c urves. Subjects are numbered for compari son of AM
`and PM studi es. Horizontal bars re present mea n ± SEM .
`
`P.M.
`
`ued absorption of enteric-coated omeprazole during
`the elimination phase. When there was log-linear
`elimination, t 112f:l was 0.7 h (n = 8, SEM 0.1) for
`morning dosage, day 1, and 1.1 h (n = 7, SEM 0.1) for
`day 5 (p < 0.05). For evening dosage, a similar trend
`was apparent (1.0 h day 1 vs . 1.5 h day 5).
`Plas,ma concentrations of omeprazole sulfone wer~
`greater after 5 days of omeprazole administration.
`The corresponding increases in sulfone AUC were
`2.1-fold (SEM 0.2, p < 0.01) and 3.9-fold (SEM 0.6,
`p < 0.02) for morning and evening dosage , respec(cid:173)
`tively.
`
`Tabl e 2. Om eprazo le and Om eprazole Sulfone Pharmacokinetic Parameters After On e or Fi ve Doses of 40 mg of Oral
`Om eprazo le
`
`Pharm aco kin eti c
`para meters
`
`Omeprazo le
`AUCo - 1 (ng · hlml)
`C pk (ng/m l)
`Tpk (h)
`
`Sulfone
`AUC0 - 1 (ng · hlml)
`Cpk (ng/ml )
`T pk (h)
`
`Morning d osage
`
`Eve ning d osage
`
`Day 1
`
`Day 5
`
`Day 1
`
`Day 5
`
`1187 (246)
`644 (110)
`3. 0 (0 .4)
`
`1286 (32 1 )
`301 (60)
`3.4 (0 .4)
`
`2223 (42 5)
`936 (177)
`2.9 (0.3)
`
`25 56 (576)
`486 (1 24)
`4 6 (0 .3 )
`
`84 2 (198)
`296 (65 )
`4. 8 (0.6)
`
`871 (240)
`227 (59)
`5. 6 (0.6)
`
`23 03 (5 66)
`705 (16 2)
`3.3 (0. 5)
`
`2338 (585 )
`353 (68 )
`4 .3 (0 .2)
`
`AUC0 1• area und er p las ma co ncentra ti o n-ti me cur ve 0 to I; Cpk· pea k p las ma concen trati o n ; T pk • time to rea ch pea k pl as ma
`concentratio n. Va lu es a re mea n ± SEM.
`
`

`
`68 PRICHARD ET AL.
`
`GASTROENTEROLOGY Vol. 88 , No. 1, Part 1
`
`Omeprazole sulfone, but not omeprazole, was de(cid:173)
`tectable in urine. On day 1, 2.7% and 6.5% of the oral
`dose was excreted for morning and evening dosage,
`respectively. Results were similar on day 5 (2 .6%
`and 5.4%).
`
`Safety Evaluation
`
`Omeprazole administration produced no de(cid:173)
`tectable side effects . Several subjects complained of
`a mild sore throat and tiredness at the end of a
`hospital day, but this could reasonably be attributed
`to the study procedures . There was no significant
`alteration of pulse rate, blood pressure, electrocar(cid:173)
`diogram, biochemical parameters , or urinary analy(cid:173)
`sis. Hematologic indices were also normal with the
`exception of slight falls in the mean erythrocyte
`count (5 .2 to 4.8 x 1012/L), hemoglobin level (146 to
`134 giL), and hematocrit reading (0.45 to 0.41 ). These
`changes (with the exception of the hematocrit rea d(cid:173)
`ing) were within the laboratory reference range, had
`reversed by the final follow-up examination, and
`were attributed to blood sampling during the course
`of the study.
`
`Discussion
`In this stud y, 5 days of omeprazole treatment
`produced a marked elevation in gastric pH that was
`sustained through out an entire day. The changes in
`24-h median pH correspond to redl!ctions in hydro(cid:173)
`gen ion activity of u p to 1200-fold. This reduction in
`hydrogen ion activity assumes greater signifi cance
`when compared w ith the mere twofold to tenfold
`change that occurs with histamine H2-receptor an(cid:173)
`tagonists (19,21 ). A similar effect with omeprazole
`given once daily in the morning was found in
`duodenal ulcer pati ents by Walt et al. (1 3) who
`obtained a median pH of 5. 3, compared with our
`24-h median pH of 5.0 for morning dosage.
`The method used in the present study for assess(cid:173)
`ing the antisecretory effects of omeprazole, the serial
`determination of intragastric pH over a prolonged
`period , has been used in a number of other cl inical
`studies of antisecretory drugs (13,19- 21) . A di sad(cid:173)
`vantage of this approach is that this method gives no
`information about the volume of secretion. The ad(cid:173)
`vantage, however, is that it gives information about
`gastric acidity under conditions of diet and activity
`that approximate normal living. It also allows the
`study of the influence of dosage time on clinically
`important variables such as drug effect and pharma(cid:173)
`cokinetics. The resulting information is relevant to
`the rational use of the drug in the clinical setting.
`Our use of a nonparametric method (Wilcoxon's
`signed-ranks test) for statistical significance testing,
`and of the median with interquartile range for pre-
`
`sentation of gastric pH and acidity data, is in contrast
`to other studies (13,19-22) . These previous studies
`used parametric tests of significance (such as analy(cid:173)
`sis of variance) , and often presented data as arithme(cid:173)
`tic means and standard errors. Because of the skew(cid:173)
`these
`ness and non-Gaussian distribution of
`parameters, the arithmetic mean ± SEM poorly de(cid:173)
`scribes the dpta, and the use of parametric tests is
`hazardous (17). For example, the arithmetic mean of
`pH and hydrogen ion activity respectively underes(cid:173)
`timates and overestimates the point of central ten(cid:173)
`dency as given by the median. In some of our data
`this discrepancy was marked.
`Gastric pH was measured after 5 days of dosage
`because the effect of omeprazole on gastric acid
`secretion reaches a plateau over this period (23).
`This may largely reflect the long half-time of inhibi(cid:173)
`tion of acid secretion of 24 h (2) , which is thought to
`be due to the persistence of omeprazole or metabo(cid:173)
`lite within the parietal cell (4 ,14,24). However, the
`delay in reaching a maximal effect on acid secretion
`is likely t() be due in part to the increasing bioavail(cid:173)
`ability of omeprazole over this time (Figure 3).
`One purpose of this study was to determine
`whether morning or evening dosagEi gave better con(cid:173)
`trol of 24-h intragastric pH. Whereas a 40-mg dose of
`omeprazole in the evening substantially elevated
`intragastric pH throughout the day and night, the
`elevation was greater overall after morning dosage,
`due to better control of acidity during the period
`from 9 AM to 8 PM. A possible explanation is that,
`after morning dosage, intracellular concentrations of
`omeprazole were higher during the day, when there
`were more stimuli to acid secretion (e.g., meals) ;
`whereas after evening dosage, these concentrations
`were maximal when stimuli to acid secretion were
`few . This finding would suggest that morning dosage
`should be the regimen of choice for future ulcer(cid:173)
`healing studies.
`Two previous reports have provided some phar(cid:173)
`macokinetic information about omeprazole in hu(cid:173)
`mans (2 ,14). In these a single dose of drug, either as a
`micronized suspension or as uncoated granules, was
`given with bicarbonate followed by repeated admin(cid:173)
`istration of bicarbonate. The purpose of this method
`of dosing was to minimize intraluminal degradation
`as omeprazole is acid-labile. The time to peak plas(cid:173)
`ma concentration was reported to be 30-40 min, and
`the plasma half-life averaged 50 min. In our study we
`have used an encapsulated enteric-coated granulate
`to minimize acid degradation. We found the plasma
`half-life after a single dose of the enteric-coated
`granulate to be similar to that previously reported
`(44 min for morning dosage) , but as expected the
`time to peak plasma concentration was delayed to
`several hours when the enteric-coated granulate was
`used. The AUC for single dosage of this granulate
`
`

`
`january 1985
`
`OMEPRAZOLE: DYNAMICS AND KINETICS 69
`
`was similar to that obtained with equiva lent doses of
`uncoated drug administered with bicarbonate (2 , 14) ,
`but considerably greater than after uncoated drug
`given without buffer (Skanberg I, personal communi(cid:173)
`cation). In addition , it was apparent in our study that
`absorption was faster when a single dose was given
`in the morning than in the evening.
`In every subject, bioavailability of omeprazole
`increased during repeated dosage, coincident with
`substantial reduction in gastric acidity. This in(cid:173)
`creased bioavailability, together with greater peak
`plasma concentrations , could theoretically be due to
`either increased absorption or decreased plasma
`clearance. In the absence of intravenous kinetic data,
`decreased clearance cannot be excluded, but given
`the acid lability of the drug it is highly likely that
`increased absorption is primarily responsible for the
`increased bioa vailabili ty.
`What significance can be put on plasma pharma(cid:173)
`cokinetic data for a drug that has sustained effects on
`its target organ long after it is cleared from plasma?
`Although there is no direct temporal relationship
`between the plasma concentration of omeprazole
`and its antisecretory effect, the AUC for this drug
`correlates well with the magnitud e of acid inhibition
`(2,14) . Thus the substantial increase in AUC, i.e ., in
`bioavailability, observed in the present study is
`likely to be reflected in increased acid inhibition,
`and alterations in drug dosage should take this
`delayed effect into account. Moreover, the increase
`in AUC with repeated dosage over several days may
`prove to have important toxicologic impli cations .
`This drug has several interesting fa cets . It has a
`prolonged effe ct on acid secretion that persists long
`after the drug has disappeared from plasma-pre(cid:173)
`sumably because it accumulates in the parietal cell.
`This sustained action allows substantial control of
`gastric acidity with only once-daily dosage. To date
`omeprazole has been free of side effects-which
`would be in keeping with it targeting to an enzyme
`specificall y found so far only in parietal cells. It
`appears to also have the unusual property of improv(cid:173)
`ing its own bioavailability with repeated dosage . It
`therefore seems likely that omeprazole, or related
`compounds, will be useful in a variety of conditions
`in which gastric acidity plays a pathogenetic role.
`
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