GASTROENTEROLOCY 1985:B8:64—9
`
`Omeprazolez A Study of Its Inhibition of
`Gastric pH and Oral Pharmacokinetics
`After Morning or Evening Dosage
`
`I-‘RICHARD, NEVILLE D. YEOMANS,
`PETER ].
`GEORGE W. MIHALY, D. BRIAN IONES, PETER ]. BUCKLE,
`RICHARD A. SMALLWOOD, and WILLIAM ]. LOUIS
`Departments of Gastroenterology and Clinical Pharmacology/Therapeutics, Division of Medicine,
`University of Melbourne, Austin Hospital. Heidelberg, Victoria, Australia and Astra
`Pharmaceuticals, North Ryde 2113. New South Wales, Australia
`
`Pharmacodynamic and pharmacokinetic studies of
`omeprazole, a new gastric antisecretory agent, were
`undertaken in 8 healthy subjects. The drug was
`administered orally as an encapsulated anterio-
`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-
`ability. The pretreatment 24-h median pH was 1.9
`{interquartile range 1.4-2.9]. After 5 days of treat-
`ment, the median 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.
`'l'his corresponded to o
`>99"/o reduction in 24-h median hydrogen ion activ-
`ity, with morning dosage having a greater effect
`[from 9 ,—\.\1 to 8 PM) {p < 0.01) than evening dosage.
`The relative bioavailobility of omepramle increased
`twofold from day ‘i
`to day 5 of treatment with
`morning dosage {p < 0.02} and tlireefold with eve-
`ning dosage {p < 0.02), suggesting that
`increased
`absorption of this acid-labile drug occurs with in-
`creasing inhibition of acid secretion. We conclude
`that this formulation of omeprazole presently being
`used in clinical trials is a highly potent antisecretorv
`
`‘I Slit-1.
`t.‘ttt-t. x\i:r:cptcrl lnly it}.
`Rt>(1ci\e(l ]anI1ar_v 2.].
`Address requests for reprints to: Neville ll Yeonians. M.l)..
`GastrocntcI'olo§,=_v Unit. Department of _\ledicint:. Austin Hospital.
`Heidelberg Z3()tH. Victoria. Austrtilia.
`This work was supported by the National Health and Medical
`Research Council of Australia.
`A })1‘(3li1i1iziai‘y Loniinunication oi part oil this \\ oil; has appeared
`as an ah.~'ti‘zu;t
`(1) and was presented at
`the Annual Scientitic
`Meeting of the (lastroenterolngical Sot:iet_v of Australia. Perth.
`Australia. l\«lav1EIttI5.
`The authors thank Dr.
`processing.
`“C 1985 by the .»'\merican Castroenteroloaical Assmziation
`U0]U~5()85r°85'$3.I$(J
`
`for help with computer
`
`lohn Mc_\Icil
`
`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 ériodeiigl 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-
`prazole in humans (2,131-'1]. and human pharmaco-
`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 biitter (2.14). As omeprazole is acid-labile.
`unprotected exposure to acidic gastric contents re-
`sults in inactivation of >50% of an oral (lose [Skiin-
`berg 1, personal communication]. Thus the torimita-
`tion of the oral preparation will have a profound
`effect on the pharmacoldnetics, and on the antisccre-
`tory effect of the drug.
`In the present study we have examined the oral
`pharmacokinetics and the gastric antisecretory activ-
`ity of omcprazolc formulated as an encapsulated.
`enteric-coated granulate. which is the form currently
`undergoing clinical trial
`(8). Two particular ques-
`tions have been considered: (:1) whether morning or
`evening atlministration of a daily 40-mg dose gives
`better control of 24-h intragastric pH. and [b] wheth-
`er the oral bioavailability oi
`this formulation in-
`creases during the initial phase of treatment as acid
`secretion declines.
`
`Lupin Exh. 1020
`
`Lupin Exh. 1020
`
`

`
`anuary 1985
`
`OMEPRAZOLE: DYNAMICS AND KINETICS 65
`
`Material and Methods
`
`Subjects
`
`‘
`
`Eight healthy male volunteers were studied. Mean
`3 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 disease. Physical examination,
`' electrocardiogram, and laboratory screen 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-
`fore administered as an encapsulated, enteric-coated gran-
`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 pharmacokinetic
`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-
`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-
`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 10F
`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-
`trode and digital pH meter [Orion Research model 611,
`Orion Research Inc., Cambridge, Mass.). The pH meter was
`calibrated with Merck standard buffers [E. Merck, Darm-
`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 were immediately
`centrifuged for 5 min and the plasma was transferred to
`plastic tubes containing 10 ,ul of 1 M Na2CO3. Urine
`samples were also 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 p.1 of 1 M Na2CO3. All
`samples of plasma and urine were stored at —20°C.
`
`Drug Assays and Pharmacokinetic
`Calculations
`
`Plasma and urine samples were assayed for ome-
`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-
`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 [C1] or 12 h
`[Ct=C12) (AUC0_,) were determined using the linear trape-
`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 AUC04 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-
`tion (Tpk) were calculated directly from the plasma con-
`centration data for each individual. Apparent elimination
`half-life [t1/2,3) 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-
`quent intervals, and patients were questioned about ad-
`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
`
`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 and evening administration of omeprazole.
`One measure of the usefulness of gastric antisecre-
`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 every 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-
`zole treatment were 0.01 and 0.04 mmol/L for morn-
`ing and evening dosage, respectively, compared with
`12.6 mmol/L for the control study. For both omepra-
`zole regimens this represents inhibition of hydrogen
`ion activity of >99%.
`The principal gastric pH and hydrogen ion activity
`data are summarized in Table 1. The highly signifi-
`cant skewness values and the large differences be-
`tween variances of the individual groups [Bartlett’s
`test, pH data: X2 = 20.6 [p < 0.001]; hydrogen ion
`activity: X2 = 744.1 [p < 0.001)] indicate that the
`data are not normally distributed and are, therefore,
`not appropriately expressed as mean : SD. Howev-
`er, to allow comparison with other studies [13,19]
`the arithmetic mean has been included in Table 1.
`
`_
`
`Pharmacokinetic Studies
`
`The mean plasma concentration-versus-time
`profiles for omeprazole on days 1 and 5 after morn-
`ing and evening dosage are shown in Figure 2.
`Pharmacokinetic parameters for omeprazole and one
`of its metabolites, omeprazole sulfone, are summa-
`rized in Table 2. The second metabolite, omeprazole
`
`Table 1. Gastric pH and HT Activity, Medians, and
`Other Population Parameters for the 24-Hour
`Period
`
`Median
`
`Interquartile Arithmetic
`range
`mean : SD Skewness
`
`Statistical Analysis
`
`Because of significant skewness [17] of the distri-
`butions of pH and hydrogen ion activity, these data have
`been presented not as means and standard errors but as
`medians with interquartile ranges. The median was a more
`representative measure of central
`location, or in other
`words of “average value,” than either the ordinary arith-
`metic mean or the geometric mean [arithmetic mean of log-
`transformed data). Other data that were normally distribut-
`ed are presented, as usual, as mean : SEM. Gastric pH and
`hydrogen ion activity were compared using distribution-
`independent nonparametric methods (Wilcoxon’s signed-
`ranks test) [17]. Before applying these methods, 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 of 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
`omeprazole 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
`
`pH
`
`Gastric
`
`0100
`
`Time
`
`(hours)
`
`Figure 1. Gastric pH-time profiles for the baseline study [open
`triangles] and after 5 days of omeprazole administra-
`tion in the morning [closed circles] or evening [open
`Circles]. Values are medians with interquartile ranges
`[n : 8]. Closed triangles, dosage times [omeprazole
`or placebo]; closed stars. main meals; open stars, small
`meals and snacks.
`
`1.9
`5.0
`4.5
`
`1.4-2.9
`3.7-6.0
`3.0-5.5
`
`pH
`Baseline
`Morning dose
`Evening dose
`H’' activity
`[mmol/h]
`26.1
`1.3—39.8
`12.6
`Baseline
`1.1
`0.001—0.2
`0.01
`Morning dose
` —
`Evening dose
`0.04
`0.003—1.0
`3.7
`
`2.3 : 1.2
`4.8 : 1.4
`4.4 : 1.7
`
`1.22“
`-0.41”
`-0.08
`
`G p < 0.001. b p < 0.025.
`
`

`
`Ianuary 1985
`
`OMEPRAZOLE: DYNAMICS AND KINETICS 67
`
`(:
`
`PM Doug:
`=>—+! Dav 1
`o—o Day 5
`
`5000
`
`4000
`
`AM Do-ago
`“"0 Day 1
`
`o—o Day 5
`
`I000:
`E
`
`P..
`
`E\
`
`u:
`
` DnmConcentration
`
`1
`
`L
`0
`
`1
`
`l
`4
`Time
`
`l
`
`1 4 I
`B
`12
`(howl)
`
`l___J
`0
`
`J
`4
`Tlmn
`
`l
`L
`8
`(houu)
`
`l
`
`.._J
`12
`
`Figure 2. Plasma concentration-time curves for omeprazole (40
`mg) on day 1 and day 5 of dosage. given AM or PM.
`Values are the mean concentration with SEM (n = 8).
`
`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-
`zole plasma concentration-time curve (AUC0_,) (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-
`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-
`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-
`nificant.
`Elimination half—lives (t1/23) of omepazole could
`not be characterized in eight of thirty-two plasma
`concentration profiles because of erratic and contin-
`
`2000
`
`1000
`
`3000 It)i<\\ l\\
`
`STUDY DAY :
`
`DOSE TIME:
`
`A.M.
`
`P.H.
`
`Figure 3. Area under the omeprazole plasma concentration~time
`curves. Subjects are numbered for comparison of AM
`and PM studies. Horizontal bars represent mean : SEM.
`
`ued absorption of enteric—coated omeprazole during
`the elimination phase. When there was log—linear
`elimination,
`t1/2,3 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).
`Plasma concentrations of omeprazole sulfone were
`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-
`tively.
`
`Table 2. Omeprazole and Omeprazole Sulfone Pharmacokinetic Parameters After One or Five Doses of 40 mg of Oral
`Omeprazole
`Evening dosage
`
`Morning dosage
`
`Pharmacokinetic
`
`parameters
`Omeprazole
`AUCU4 (ng - h/ml)
`Cpk (ng/ml]
`Tpt (h)
`
`Sulfone
`
`Day 1
`
`1187 (246)
`644 (110)
`3.0 (0.4)
`
`Day 5
`
`2223 (425)
`936 (177)
`2.9 (0.3)
`
`Day 1
`
`842 (198)
`296 (65)
`4.8 (0.5)
`
`Day 5
`
`2303 (566)
`705 (162)
`3.3 (0.5)
`
`2338 (585)
`871 (240)
`2556 (576)
`1286 (321)
`AUC(,,, (ng - h/ml)
`353 (68)
`227 (59)
`486 (124)
`301 (60)
`CD5. (ng/ml)
`
`Tpk (h) 4.3 (0.2) 3.4 (0.4) 4.6 (0.3) 5.6 (0.6)
`
`
`
`
`AUCU ,. area under plasma concentration-time curve 0 to 1: CV... peak plasma concentration; T,,k,
`concentration. Values are mean : SEM.
`
`time to reach peak plasma
`
`
`
`

`
`68 PRICHARD ET AL.
`
`GASTROENTEROLOGY Vol. 88, No. 1, Part 1
`
`Omeprazole sulfone, but not omeprazole, was de-
`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-
`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-
`diogram, biochemical parameters, or urinary analy-
`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 g/L), and hematocrit reading (0.45 to 0.41). These
`changes [with the exception of the hematocrit read-
`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 study, 5 days of omeprazole treatment
`produced a marked elevation in gastric pH that was
`sustained throughout an entire day. The changes in
`24-h median pH correspond to reductions in hydro-
`gen ion activity of up to 1200-fold. This reduction in
`hydrogen ion activity assumes greater significance
`when compared with the mere twofold to tenfold
`change that occurs with histamine H2-receptor an-
`tagonists (19,21). A similar effect with omeprazole
`given once daily in the morning was found in
`duodenal ulcer patients by Walt et al.
`(13) 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-
`ing the antisecretory effects of omeprazole, the serial
`determination of intragastric pH over a prolonged
`period, has been used in a number of other clinical
`studies of antisecretory drugs (13,19—21). A disad-
`vantage of this approach is that this method gives no
`information about the volume of secretion. The ad-
`
`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-
`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-
`sis of variance), and often presented data as arithme-
`tic means and standard errors. Because of the skew-
`ness
`and non-Gaussian distribution of
`these
`
`parameters, the arithmetic mean : SEM poorly de-
`scribes the data, and the use of parametric tests is
`hazardous (17). For example, the arithmetic mean of
`pH and hydrogen ion activity respectively underes-
`timates and overestimates the point of central ten-
`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-
`tion of acid secretion of 24 h (2), which is thought to
`be due to the persistence of omeprazole or metabo-
`lite within the parietal cell (4,14,24). However, the
`delay in reaching a maximal effect on acid secretion
`is likely to be due in part to the increasing bioavail-
`ability of omeprazole over this time (Figure 3).
`One purpose of
`this study was to determine
`whether morning or evening dosage gave better con-
`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-
`healing studies.
`Two previous reports have provided some phar-
`macokinetic information about omeprazole in hu-
`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-
`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-
`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
`
`

`
`.;Ianuary 198 5
`
`OMEPRAZOLE: DYNAMICS AND KINETICS 69
`
`was similar to that obtained with equivalent doses of
`uncoated drug administered with bicarbonate (2.14),
`but considerably greater than after uncoated drug
`given without buffer (Skanberg 1, personal communi-
`cation]. In addition, it was apparent in our study that
`absorption was faster when a single dose was given
`1 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-
`creased bioavailability, together with greater peak
`I plasma concentrations, could theoretically be due to
`either
`increased absorption or decreased plasma
`clearance. In the absence of intravenous kinetic data,
`
`A
`
`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 bioavailability.
`What significance can be put on plasma pharma-
`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 magnitude 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 implications.
`This drug has several interesting facets. It has a
`prolonged effect on acid secretion that persists long
`after the drug has disappeared from plasma—pre-
`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
`specifically found so far only in parietal cells.
`It
`appears to also have the unusual property of improv-
`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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