Research, Vol. 7, No. 7, 1990
`Pharmaceutical
`
`Report
`
`Upper Gastrointestinal (GI) pH in Young, Healthy Men
`
`
`and Women
`
`Jennifer B. Dressman, 1•4 Rosemary R. Berardi, 1 Lambros C. Dermentzoglou,
`
`1
`
`Tanya L. Russell/ Stephen P. Schmaltz,2 Jeffrey L. Bamett,3 and Kathleen M. Jarvenpaa2
`
`Received May 8, 1989; accepted January 15, 1990
`
`The pH in the upper gastrointestinal tract of young, healthy men and women was measured in the
`
`
`
`
`
`
`fasting state and after administration of a standard solid and liquid meal. Calibrated Heidelberg cap­
`
`
`sules were used to record the pH continuously over the study period of approximately 6 hr. In the
`
`
`fasted state, the median gastric pH was 1. 7 and the median duodenal pH was 6.1. When the meal was
`
`
`
`
`administered the gastric pH climbed briefly to a median peak value of 6. 7, then declined gradually back
`
`
`to the fasted state value over a period ofless than 2 hr. In contrast to the pH behavior in the stomach,
`
`
`
`
`feeding a meal caused a reduction in the median duodenal pH to 5.4. In addition, there was consid­
`
`
`
`
`basis. The pH in the duodenum duodenal pH on an intrasubject erable fluctuation in the postprandial
`
`
`did not return to fasted state values within the 4-hr postprandial observation period. There was no
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`
`
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`tendency for the duodenal pH to be related to the gastric pH in either the fed or fasted phases of the
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`
`
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`study. Furthermore, pH in the upper GI tract of young, healthy subjects appears to be independent of
`
`
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`gender. The differences in upper GI pH between the fasted and the fed state are discussed in terms of
`
`
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`dosage form performance and absorption for orally administered drugs.
`KEY WORDS: gastric
`
`
`
`carryover pH; food effects.
`
`pH; duodenal pH; fasted state pH; fed state pH; young adults; gender effects;
`
`INTRODUCTION
`
`tinuous monitoring under fasting and fed conditions in the
`
`
`
`
`
`same group and at both gastric and duodenal locations. In
`Since small changes in the GI pH profile can af ect dos­
`
`
`particular, the pH in the mid to distal duodenum has re­
`
`
`age form performance, drug dissolution, and drug absorption
`
`
`
`ceived little attention. A further problem is that most of the
`
`
`(1-5), it is important for the formulator to know the range of
`
`
`meals studied were not designed to resemble the average
`usual values for GI pH and how it varies under normal phys­
`et al. (6,7),
`North American diet. Only Malagelada
`McCloy
`
`iological conditions. There have been numerous previous
`
`
`et al. (8), and Savarino et al. (9) have attempted to study pH
`
`
`
`studies specifically designed to examine pH in the upper GI
`
`
`
`
`response to ordinary solid/liquid meals. Moreover, the num­
`
`
`tract (6-23). However, the experimental protocol (meals,
`
`
`
`ber of subjects in most of the studies is relatively small, most
`
`
`
`
`method of measurement, duration of monitoring period, fre­
`
`
`
`of the studies used predominantly male subjects and there
`
`quency of sampling, etc.) varied widely among these studies,
`
`
`
`
`was usually little restriction on the subject age range.
`
`
`making it difficult to compare the results obtained and to
`
`In this article, we report data for fed and fasted GI pH
`
`interpret them in terms of the pH to which a dosage form
`
`
`
`in a total of 34 healthy, young subjects (24 subjects for the
`
`
`would be exposed under normal dosing conditions. In addi­
`
`
`
`
`gastric phase and 22 subjects for the duodenal phase). The
`
`tion, in some of the studies, there was a wide range of sub­
`
`
`
`data were obtained using a continuous monitoring device,
`ject ages or a high mean subject age. This is an important
`
`
`the Heidelberg capsule. Continuous recording of data al­
`
`
`
`point since other studies have indicated that increasing age is
`
`
`lowed us to better characterize peaks and fluctuations in pH
`
`associated with changes in GI pH (24,25).
`
`and to follow the functional form of the rate of return to
`
`
`
`None ofthe previous studies have measured pH by con-
`
`
`
`baseline after a meal. A standard solid/liquid meal was given
`
`
`to assess the pH response that might be typical for the North
`
`American diet. The study design also permitted the investi­
`1 College of Pharmacy,
`University of Michigan, Ann Arbor, Mich­
`
`
`
`
`gation of correlation between gastric pH values and duode­
`igan 48109-1065.
`nal pH values within specific subjects.
`
`The information ob­
`2 Clinical
`Research Center, University of Michigan, Ann Arbor,
`
`
`
`
`tained from these studies is intended to help identify situa­
`
`Michigan 48109 1065.
`
`tions in which drug bioavailability might vary as a result of
`3 Department
`
`
`
`of Internal Medicine, University of Michigan, Ann
`
`
`pH changes associated with normal physiological function of
`
`Arbor, Michigan 48109 1065.
`4 To whom correspondence
`should be addressed.
`the upper GI tract.
`
`
`
`
`
`
`
`0724-8741190/07()(H}756$06.00/0 © 1990 Plenum Publishing Corporation
`
`756
`
`

`
`Upper GI pH in Young Adults
`
`757
`
`MATERIALS AND METHODS
`
`Subject Selection
`
`Fasting pH in the body of the stomach_ was
`the subjects.
`for 1 hr in al 24 subjects.
`recorded
`
`Then a standard meal
`
`
`consisting of 6 oz of hamburger, 2 slices of bread, 2 oz of
`
`hash brown potatoes, 1 tbsp each of ketchup and mayon­
`
`
`
`The study was conducted in the Clinical Research Cen­
`
`naise, 1 oz each of tomato and lettuce and 8 oz of milk (for
`
`
`
`ter of The University of Michigan Hospitals on an outpatient
`
`
`a total of 1000 Kcal) was given. Subjects were required to
`
`
`basis, with approval of the Institutional Review Board for
`
`
`consume the meal within 30 min. Postprandial gastric pH
`
`
`
`
`studies involving human subjects. All participants gave writ­
`
`
`was monitored for 4 hr after completion of the meal, then the
`
`
`
`
`ten informed consent. Thirty-four healthy volunteers (18 fe­
`capsule was retrieved orally.
`
`male, 16 male), with a mean age of 25 years (range, 21-35
`Phase B. The participants
`fasted (with only water per­
`
`
`
`years), participated in the study. Twelve subjects completed
`
`mitted) for at least 12 hr before swallowing a tethered
`
`
`both phases, twelve subjects completed only the gastric
`
`
`
`Heidelberg capsule. Gastric pH was monitored until the cap­
`
`
`
`phase, and ten subjects completed only the duodenal phase
`
`sule emptied into the small intestine, an event marked by a
`
`
`of the study. None of the participants had a history or any
`
`
`
`rapid, unreversed elevation in pH accompanied by an in­
`
`
`clinical or laboratory evidence of gastrointestinal disease.
`
`crease in tether length. After the capsule emptied from the
`
`The health status of each subject was confirmed by a general
`
`
`stomach, it was allowed to travel approximately 10-15 em
`
`
`
`physical examination and routine screening of blood samples
`
`farther (i.e., to the mid to distal region of the duodenum).
`
`for renal and hepatic function. None were taking medica­
`
`The position was fixed by taping the tether to the subject's
`
`tions on a chronic basis. Smoking, alcohol, and all medica­
`
`cheek. Tether length at this position ranged from 65 to 85
`
`tions were discontinued for 3 days prior to and throughout
`
`
`em. The correspondence of this tethering procedure to the
`each study phase.
`
`D3-D4 region of the duodenum was verified by fluoroscopy
`
`
`
`in 12 subjects. Fasting pH in the duodenum was recorded for
`
`
`1 hr in 12 subjects and 30 min in 10 subjects. Then a standard
`
`
`meal identical to that administered in Phase A was given.
`Continuous determination of pH with time was accom­
`
`
`
`
`Postprandial pH in the duodenum was monitored for 4 hr
`
`
`
`plished using a radiotelemetric device, the Heidelberg cap­
`
`after completion of the meal, then the capsule was retrieved
`
`
`
`sule (10-12). The device consists of a battery-operated high­
`orally.
`
`
`
`frequency radio transmitter and a pH electrode housed in a
`
`
`
`
`nondigestible acrylic capsule 7 mm in diameter and 20 mm in
`
`
`
`
`length. The frequency of transmission changes with the pH
`
`
`of the capsule's environment and can be calibrated using
`The pH measurements for the study were stored at 15-
`
`
`standard buffer solutions. The subject wears an antenna
`
`
`sec intervals using a program written in BASIC for the Apple
`
`
`
`strapped around the waist to receive the radio signal, which
`
`lie computer. Data were divided into three periods (fasted,
`
`
`
`is then converted back to pH and recorded continuously as
`
`
`during the meal, and postprandial) for both the gastric phase
`
`
`
`
`a function of time on an analogue recorder and digitally at
`
`
`and the duodenal phase of the study. Data were collected for
`
`
`15-sec intervals on an Apple lie computer (Apple Computer
`
`1 hr in the fasted state and for 4 hr in the postprandial state.
`
`Co., Cupertino, CA).
`
`
`Data were also collected during meal ingestion, a period
`In vitro studies
`were conducted previously to confirm
`
`
`which varied between 12 and 30 min.
`
`the pH unit accuracy to within ±0.5 pH unit over an 8-hr
`For the descriptive part of the data analysis, the data are
`
`
`study period (13). The capsule battery was activated with
`
`
`displayed as box-whisker plots (26), which list the median
`
`normal saline the morning of the study. Immediately prior to
`
`
`and interquartile range for each subject or for pooled data
`
`
`administration, the capsule unit was calibrated in pH 1 and 7
`
`
`(see Fig. 1), or as frequency distributions. In all cases where
`
`
`buffer solutions maintained at 37°C. The capsule was teth­
`
`
`
`overall median values are reported, they are calculated from
`
`
`ered using surgical thread (Supramid Extra 2-0, S. Jackson
`
`
`
`
`the subjects' individual medians. Individual medians were
`
`
`
`Inc., Alexandria, VA) to regulate capsule placement during
`based on al data points of a subject
`calculated
`in each spec­
`
`
`the study and to facilitate oral retrieval. At the end of each
`
`ified phase. Interquartile ranges show the diference be­
`
`
`
`study day, the capsule was recovered and its response to pH
`
`
`tween the individual first and third quartiles. The frequency
`
`
`1 and 7 buffers checked against the prestudy values. The
`
`
`distribution plots show the percentage of the pooled data
`
`
`response was required to be within 0.5 pH unit of the pre­
`
`
`study values for results to be included in the data analysis.
`
`pH Measuring System
`
`Data Analysis and Statistical Considerations
`
`Study Protocols
`Phase A. The participants fasted (with only water per­
`
`95,. confidence inlerYal
`
`I
`ahoul lito median
`
`mitted) for at least 12 hr before swallowing a tethered
`
`
`Heidelberg capsule. After the capsule had traveled approx­
`
`imately 50 em, its position was fixed by taping the tether
`
`
`thread to the subject's cheek. Position in the body of the
`
`
`stomach was indicated by a combination of tether length and
`
`
`
`continuous recording of normal gastric pH (approximately
`Fig. 1. Typical form of the box-whisker
`
`pH 3 or lower) and was verified by fluoroscopy in twelve of
`plot.
`
`lnlerquartile
`range
`
`

`
`758
`
`Dressman et a/.
`
`A
`
` I
`
`
`
`3
`
`2
`
`collection, i.e., fasted state, during the meal and postpran­
`
`above or below specific pH values. The median absolute
`dial.
`
`
`
`deviation (MAD) was used to describe variability. This pa­
`For all tests, a P value <0.05 was considered signifi­
`
`
`rameter is defined as the median of the absolute deviation
`
`
`
`cant. The statistical software packages Midas, Statview, and
`
`
`from the individual medians and was calculated for each
`
`BMDP were used for the analysis of all data.
`
`
`
`subject for fasting, during the meal, and postprandial periods
`
`
`in both the gastric and the duodenal phases. The MAD was
`
`used because it is a robust estimate of the spread of a dis­
`RESULTS
`
`tribution (27).
`For the construction of the 5-min interval box-whisker
`
`
`Typical pH Profiles
`
`plots, each subject's data were divided into 5-min periods
`Figure 2 shows typical gastric and duodenal pH profiles.
`
`
`
`
`
`and the median of each successive period was computed.
`In the fasted state, there were periods during which gastric
`
`Each box in such a plot shows the between-subjects grand
`
`
`pH remained steady, while at other times there were fluctu­
`
`median for the 5-min interval. Since the meal period varied
`
`ations during which the pH was elevated to higher values.
`between 20 and 30 min, during the meal data were not in­
`
`
`This kind of behavior was observed to a varying degree in
`
`cluded in the 5-min interval plots.
`
`
`
`almost all gastric preprandial profiles, usually for a period of
`
`
`
`Time-series and spectral analyses (28) were performed
`
`
`about 1 to 1 5 min (average duration, 7 ± 6 min). High pH
`
`
`on fasting and postprandial data, smoothed by condensing
`
`values were attained while the meal was being ingested.
`
`
`
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`into 5-min medians, to determine any temporal effects. To
`
`
`
`
`Postprandially, the gastric pH decreased gradually over time
`
`
`
`diagnose periodicity in the time domain, time-series analysis
`and, in most cases, returned to the fasted state levels within
`
`
`
`was initially performed. Wherever the results were ambigu­
`
`the 4-hr period of monitoring. In the duodenum the pH re-
`
`
`
`
`ous, spectral analysis to look for autoregressive patterns and
`
`
`
`check for periodicity in the frequency domain followed. In
`
`
`no case were any periodic temporal effects detected.
`
`
`The gastric postprandial phase data for each subject
`
`
`were then fitted to two-parameter exponential equations.
`6
`
`
`
`The two parameters (starting pH value and first-order rate
`
`constant for the rate of return of pH to the premeal value)
`5
`
`
`were tested for normality and found to be normally distrib­
`
`
`uted. Subsequently, the mean value of each parameter was
`4
`
`
`
`used in the general equation, which empirically describes the
`
`
`change in postprandial gastric pH with time. The time to
`
`return to a specific pH after the meal was finished, in the
`
`
`
`gastric postprandial phase, was estimated from 2-min me­
`
`dian smoothed data by reading the first time at which the pH
`
`
`of interest was reached postprandially. In cases where the
`pH did not return to a specific value, an entry of 240 min
`
`
`corresponding to the whole 4-hr monitoring period was re­
`
`
`
`corded and used for subsequent analysis (right data censor­
`-1
`ing). Those cases where the pH was already below the spe­
`
`
`cific value of interest when the postprandial period started
`
`were omitted from the time-to-return-to-pH analysis.
`
`
`Nonparametric statistical procedures were used to ana­
`6
`
`
`lyze the data since, regardless of transformation, the pH
`
`
`
`
`distributions deviated considerably from normality, as deter­
`5
`
`
`mined by the Kolmogorov-Smirnov normality test (29). Spe­
`
`
`cifically, the data from 50% of the subjects in the fasted
`4
`
`
`
`gastric, 64% of the subjects in the fasted duodenal, 29% of
`
`
`
`the subjects in the gastric postprandial, and 41% of the sub­
`
`jects in the postprandial duodenal phase were nonnormal.
`
`
`Postprandial, during the meal, and fasted duodenal medians
`
`
`were compared using Wilcoxon's signed-rank test (20).
`2
`
`
`Gender differences in the parameters of the monoexpo­
`
`nential model were evaluated using the unpaired Student t
`
`
`
`test (30) since those data were found to be normally distrib­
`uted. For each phase of the study, median values for male
`
`
`and female subjects were compared using Wilcoxon's rank­
`-1
`2
`
`
`sum (Mann-Whitney l.1) test (30). Spearman's rank correla­
`Tim• (hours)
`Fig. 2. Typical pH profiles in gastric
`
`
`tion coefficient (31) for the medians was calculated to deter­
`(upper panel) and duodenal
`
`mine whether there was a carryover effect between the gas­
`
`(lower panel) phases of the study for subject J. L. Meal administra­
`
`tric and the duodenal pH values in each of the phases of data
`tion is marked by M.
`
`0
`
`2
`Time (hours)
`
`3
`
`
`4
`
`0
`
`B
`
`4
`
`3
`
`

`
`Upper GI pH in Young Adults
`
`759
`
`mained relatively constant in the fasted state. In contrast,
`
`
`
`
`
`wide fluctuations in duodenal pH were observed during the
`
`
`
`
`postprandial period. The usual duodenal pH appeared to be
`
`
`lower in the postprandial than in the fasting state, and in
`
`most cases there was no return to the fasted state pattern
`
`
`within the 4-hr postprandial observation period.
`
`Gastric Data
`
`
`
`The overall median fasting pH was 1. 7, with an inter­
`
`
`
`quartile range of pH 1.4-2.1. During the meal, the pH in­
`
`creased to a median value of 5.0 with an interquartile range
`
`
`of pH 4.3-5.4. The peak value was 6.7 (6.4--7.0). Figure 3
`
`
`shows the pH frequency distribution in the fasted state and
`
`during the ingestion of the meal. Figure 4 shows the box­
`60 90 120 150 180 210 240
`lime (minuf•$)
`
`whisker plot for the postprandial period in 5-min intervals
`
`
`using data pooled from all subjects, beginning at the end of
`Fig. 4. Box whisker plots for pooled data from three 15-min inter­
`
`
`
`the meal. The first three boxes correspond to the 15-, 30-,
`
`
`vals prior to meal administration and at 5 min intervals postprandi­
`
`and 45-min intervals in the fasted state. Values of pH re­
`
`ally for the gastric phase of the study.
`
`corded during the meal were not included, as the period of
`
`
`ingestion varied from 12 to 30 min. The general trend of the
`with an interquartile range of pH 5.8- 6.5. During the meal
`
`
`
`
`
`gastric postprandial pH data was to decline gradually from a
`
`
`the overall median pH was 6.3 (interquartile range of 6.0-
`
`
`near-neutral peak pH. The postprandial pH data were sub­
`
`
`
`6.7). Time-series analysis showed that duodenal postpran­
`
`
`
`sequently fitted to a two-parameter exponential equation,
`
`
`dial data did not exhibit any periodicity or other temporal
`
`
`effects but, rather, that pH fluctuated randomly around a
`pH = 4.13 . e o.oosr
`( 1 )
`
`grand median value of 5.4. Individual medians varied from
`
`pH 4.9 to pH 6.0. The pH values fluctuated from a minimum
`Table I presents the time taken to return to pH 5 , 4, 3 , and
`
`
`of pH 3.1 to a maximum of pH 6.7 (overall median values).
`
`
`
`2 postprandially. The means, standard deviations, medians,
`
`
`Comparison of duodenal pH in the three phases showed that
`and ranges are shown.
`
`
`pH was highest during ingestion of the meal and lowest in the
`
`
`postprandial period. Differences between phases reached
`
`significance in each case.
`The overall median fasting pH was determined to be 6.1,
`
`
`
`
`
`
`Duodenal Data
`
`90
`
`80
`
`70
`
`60
`
`c:
`
`.! ,.,
`CD 50
`!! &
`40
`
`30
`
`20
`
`10
`
`
`
`Correlation Between Gastric and Duodenal pH
`
`Correlation coefficients were below the critical value for
`
`
`
`
`
`significance between fasted gastric and duodenal pH and
`
`
`
`between postprandial gastric and duodenal pH.
`
`Variability
`
`The ratio of highest to lowest median absolute deviation
`
`
`
`(MAD) was 17: 1 for the gastric fasted state pH, indicating
`
`
`
`considerable differences in pH variability between subjects.
`
`Variability in gastric and duodenal pH during the meal also
`
`
`
`
`showed large differences between subjects, with the ratio of
`
`
`
`largest to smallest being 1 2: 1 for the gastric and 1 1: 1 for the
`
`
`
`duodenal study. In contrast, the range of variability for the
`
`
`postprandial phases was relatively small, with ratios of 5:1
`
`
`
`and 7:2 for the gastric and duodenal studies, respectively.
`
`
`
`
`
`Likewise, little intersubject variability was observed for the
`
`
`fasting phase of the duodenal study, where the MAD ratio
`
`Table I. Time to Return to Specific pH Values, After Completion
`of
`
`the Standard Meal (Minutes)
`
`2
`
`3
`
`4
`
`5
`pH
`pHS
`Fig. 3. Frequency
`distribution plots for pooled gastric pH in the
`
`
`pH4
`
`fasted state (A) and during ingestion of the meal (B). The percentage
`pH3
`
`
`
`of data falling below a given pH value can be obtained by reading the
`pH2
`
`
`percentile corresponding to the pH of interest.
`
`6
`
`7
`
`8
`
`Mean± SD
`
`Median
`
`Range
`
`11 ± 10
`28 ± 24
`56 ± 41
`107 ± 70
`
`8
`14
`45
`96
`
`2-34
`4-74
`2-158
`8-240
`
`

`
`760
`
`Dressman et al.
`
`DISCUSSION
`
`Gender Effects
`
`gest that it would be unwise to recommend administration
`was 4:1 . With regard to intrasubject variability, there was a
`
`
`
`
`with meals for formulations/drugs which require acidic pH
`
`
`higher variation in the gastric phase during the meal and in
`
`
`
`
`for rapid release. Further, enteric-coated preparations may
`
`
`the duodenal postprandial phase, relative to the other
`drug in the stomach if ingested
`
`partially release
`during meal
`phases.
`
`
`
`intake. Depending on their composition, other meals may
`
`result in a lower peak pH, but the prescriber must guard
`
`
`against worst-case pH conditions.
`With regard to gender effects, data were not signifi­
`
`After the meal was completed, the pH gradually de­
`
`
`
`cantly different between men and women in any of the
`
`
`clined until fasted-state pH was reestablished. Decline in pH
`phases of the study.
`
`
`
`is most likely a function of both the ability of the meal to
`
`
`
`stimulate gastric acid secretion and the rate at which the
`
`
`meal is emptied from the stomach. The information in Table
`
`
`
`I indicates that after meal ingestion is complete, the pH
`Fasting gastric pH has been well studied (6,7,9,14-19),
`
`
`
`
`quickly falls back below pH 5 and then gradually declines
`
`
`
`
`with little variation among the results obtained. The gener­
`back to fasted state values over a period of less than 2 hr.
`
`
`
`ally accepted value for fasting gastric pH is approximately
`
`The fact that we observed a somewhat longer time for res­
`
`
`pH 2. We observed a median fasted gastric pH of pH 1.7,
`
`
`toration of the fasting state pH ( - 1 20 min, versus 60 min in
`
`
`
`with a considerable degree ofintersubject variation. The fre­
`
`
`
`most reported studies) is probably due partly to the large
`
`
`quency distribution in Fig. 3 indicates that the fasted-state
`
`meal size (long emptying time) and partly to the high buffer
`
`gastric pH is below pH 2 68% of the time and below pH 3
`
`
`capacity of the meal. There was considerable subject-to­
`
`
`90% ofthe time. In young healthy volunteers, pH above 4 is
`
`
`
`subject variation in the rate of return to premeal values. In
`
`evident about 6% of the time, while pH above 6 is very rare
`
`
`
`most people, though, medications administered 2 hr or more
`in the fasted state.
`
`
`
`
`after meals should encounter gastric pH conditions similar to
`
`During the 1-hr observation period in the fasted state,
`
`the fasted state. Enteric-coated dosage forms with a disso­
`
`
`
`
`episodes of elevated pH were recorded in the majority of
`
`
`lution pH of 5 or greater could be safely administered 20 min
`
`
`
`subjects. It is postulated that this may be due to contact of
`
`
`after meal intake is complete. These probably represent
`
`the measuring device with the stomach wall. Alternatively,
`
`maximum times as most other meals would be smaller and/or
`
`there may be a genuine elevation of the lumenal pH. The
`have lower buffer capacity.
`
`
`
`
`latter would explain why some "tubeless gastric pH analy­
`Fasting duodenal pH has been most extensively mea­
`
`
`
`
`
`
`sis" and single-point aspiration studies (20) reported a higher
`
`sured in the duodenal bulb (6,8,15,17- 1 9,21). The wide vari­
`
`
`
`
`incidence of raised gastric pH than multipoint aspiration or
`
`ation in mean pH values reported may be due to wide tem­
`
`
`continuous monitoring study designs.
`
`poral and positional fluctuation in pH in this area of the
`
`
`Postprandial gastric pH (6,7,9,1 7- 1 9) is not as well char­
`
`
`duodenum, which makes it difficult to determine an accurate
`
`
`acterized as fasted-state data. The only groups in this series
`mean value (22).
`which studied pH changes after a normal solid meal were
`
`
`Savarino et al. (9) and Malagelada et al. (6,7). The pH re­
`There have been only three studies which investigated
`
`pH in the mid to distal region of the duodenum. Of these
`
`
`sponse during and immediately after the meal is ingested is
`
`
`three, two (6,15) used older subjects, with ages ranging up to
`
`
`particularly poorly characterized because data were either
`
`
`63 and 67, respectively. Unlike the stomach, the fasted mid
`
`
`
`collected by pooling aspirates or reported only at certain
`
`intervals. These methods tend to obscure important data
`
`
`
`to distal duodenum appears to be very stable with respect to
`
`pH. This was illustrated by the low MAD values in this
`such as peak pH value and time of peak pH. Return to fast­
`
`phase of the study. The median pH of 6.1 (interquartile range
`
`
`
`
`ing pH in the studies listed generally occurred within 60 min
`
`
`
`
`of 5.8 to 6.5) was similar to previously reported results for
`
`
`after the meal. In our study, ingestion of the meal resulted in
`
`the distal duodenum. Figure 5 indicates that the pH in the
`
`
`
`a substantial elevation of the gastric pH. The median peak
`fasted state is above pH 5 more than 90% of the time but
`
`
`
`pH following ingestion of the hamburger, hashed brown po­
`rarely exceeds pH 7.
`and milk meal was 6.7, with an interquartile
`tatoes,
`range of
`There are only two studies which have reported values
`
`
`
`6.4 to 7.0. This can most likely be attributed to the buffering
`
`
`for postprandial pH in the mid to distal duodenum. Of these
`effect of the fluid (in this case, milk) and food ingested.
`two, Ovesen et a[. 's ( 1 8) used a liquid meal rather than a
`
`When the meal was homogenized, its pH was 5.72. Other
`
`
`standard solid meal. The other (6) included older subjects
`
`meals with lower-pH fluids such as coffee, cola drinks, fruit
`
`
`
`and reported pH of pooled intestinal aspirates rather than
`
`
`juices, etc., may not buffer the gastric pH to as high a peak
`
`
`using a continuous monitoring device. Pooling samples over
`
`
`
`pH. Malagelada and co-workers' (6,7) studies used water as
`
`the fluid portion of the meal, while Savarino et al. did not
`
`
`
`collection intervals of several minutes makes it difficult to
`
`
`
`observe the fluctuations in duodenal pH which occur in the
`
`
`
`describe the meal contents. Some of the fluid-only meals
`
`
`
`fed state (22). In contrast to the gastric results, the pH at mid
`
`
`
`
`consisted of chocolate milk, which contains alkaloids such
`
`to distal duodenum was observed to be lower postprandially
`
`
`as caffeine. These alkaloids may augment the normal nutri­
`
`
`
`than in the fasting state. Furthermore, in contrast to the
`
`
`ent stimulation of gastric acid secretion.
`
`
`duodenal bulb region, the low pH appears to be maintained
`
`During meal ingestion, the pH was above pH 4 73% of
`
`throughout an extended observation period.
`the time (Fig. 3), above pH 5 45% of the time and above pH
`
`Upon ingestion of the meal, a brief period of elevated
`6 20% of the time. The time taken to ingest the meal was
`
`
`duodenal pH was often observed. This can be attributed to
`
`between 1 2 and 30 min for all subjects. The peak pH usually
`
`
`
`the cephalic phase of pancreatic bicarbonate secretion ( 1 3).
`
`
`
`occurred within the first 5 min of eating. These results sug-
`
`

`
`Upper GI pH in Young Adults
`
`761
`
`90
`
`80
`
`70
`
`ACKNOWLEDGMENTS
`
`This work was supported by MOl-RR-00042 (through
`
`
`
`
`
`the Clinical Research Center at The University of Michigan
`
`
`
`Hospitals) and GM 38888 from the National Institutes of
`Health and by an Upjohn Research Award. Lambros Der­
`
`
`
`
`mentzoglou and Tanya Russell were partially supported by
`Pfizer, Inc., fellowships.
`The authors wish to thank John Wlodyga and Mary
`
`
`
`Margaret Myers for their excellent technical assistance in
`
`
`the clinic, and Henry Lau for the BASIC program for digital
`
`storage of data.
`
`60
`�
`"E 50
`0 (j; c.
`40
`
`..
`
`30
`
`20
`
`10
`
`2
`
`3
`
`5
`
`6
`
`7
`
`8
`
`REFERENCES
`l. P. Shore, B. Brodie, and A. Hogben. J. Pharmacol. Exp. Ther.
`119:361 368 (1957).
`
`2. D. Winne. J. Pharmacokin. Biopharm. 5:53 94 (1977).
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`
`and A. Ejima. Int. J. Clin. Pharmacol. Ther. 20:16&-170 (1982).
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`Takagishi, T. Ogura, K. Tomita, S. Inoue, and M. Zaizen. Int.
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`J. Pharm. 23:277 288 (1985).
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`6. J.-R. Malagelada, G. F. Longstreth, W. Summerskill, and V. L.
`
`
`
`
`Go. Gastroenterology 70:203 210 (1976).
`pH during plots for pooled duodenal Fig. 5. Frequency distribution
`
`
`
`
`7. J. R. Malagelada, V. L. W. Go, T. Deering, W. Summerskill,
`
`ingestion of the meal (A), in the fasted state (B), and in the post­
`
`and V. L. Go. Gastroenterology 73:989 994 (1977).
`
`prandial state (C).
`
`
`8. R. McCloy, G. Greenberg, and J. Baron. Gut 25:38&-392 (1984).
`
`
`
`9. V. Savarino, G. S. Mela, P. Scalabrini, A. Sumbarez, G. Fera,
`and G. Celie. Digest. Dis. Sci. 9:1077 1080 (1988).
`
`
`10. D. R. Yarborough, J. C. Mcllhany, et al. Am. J. Surg. 117:185
`The pH in the postprandial phase in the duodenum is con­
`
`191 (1%9).
`
`siderably lower than in the fasted state. The pH is below 5
`
`
`28% of the time in the fed state, compared with 8% in the
`482 (1969).
`12. J. M. Williamson, R.I. Russell, and A. Goldberg.
`
`
`Scand. J.
`
`fasted state. The equivalent numbers for time spent below
`
`Gastro. 4:369 375 (1969).
`
`pH 6 are 80 and 38%, respectively. Drugs for which the pH
`13. C. A. Youngberg, R. R. Berardi, W. F. Howatt, M. C. Hy­
`
`
`
`
`of half-maximal absorption lies in the pH 5 to 7 range may
`neck, G. L. Amidon, J. H. Meyer, and J. B. Dressman.
`Digest.
`
`
`
`therefore be absorbed at different rates if given in the fed
`Dis. Sci. 32:472-480 (1987).
`
`14. G. Dotevall. Acta Med. Scand. 170:59-67 (1961).
`
`state as opposed to the fasted state. Formulations with pH­
`
`15. A. Benn and W. T. Cooke. Scand. J. Gastro. 6:313 317 (1971).
`
`
`
`sensitive release profiles may also be expected to perform
`
`16. H. W. Davenport. A Digest of Digestion, 2nd ed., Yearbook
`
`
`differently under fasted-versus fed-state conditions.
`
`
`Medical, Chicago, 1978, p. 103.
`
`During and following the meal, there were randomly
`17. S. Hannibal and S. J. Rune. Eur. J. Clin. Invest. 13:455-460
`
`
`spaced fluctuations in duodenal pH. These can be explained
`(1983).
`18. L. Ovesen, F. Bendtsen, U. Tage Jensen, N. T. Pedersen,
`
`
`
`
`by the periodic emptying of chyme from the stomach, fol­
`
`B. R. Gram, and S. J. Rune. Gastroenterology 90:958 962
`
`
`lowed by reneutralization with pancreatic bicarbonate.
`(1986).
`
`Overall, the pH in the postprandial phase of the duodenal
`
`19. F. Bendtsen, B. Rosenkilde Gram, U. Tage Jensen, L. Ovesen,
`
`
`
`study appears to be somewhat lower and much more vari­
`
`
`and S. J. Rune. Gastroenterology 93:1263 1269 (1987).
`
`20. H. L. Segal, L. L. Miller, and J. J. Morton. Proc. 5th Natl. GI
`
`
`able than the pH observed in the fasting state. The fluctua­
`Cancer Conf., 1953, p. 1079.
`
`
`tions in pH have been observed previously in the distal du­
`21. S. J. Rune and K. Viskum. Gut 10:569 571 (1969).
`
`
`
`odenum when continuous monitoring was employed (18).
`
`22. S. J. Rune. In Mageneund Magenkrankheiten, W. Domschke
`
`There was no trend for those with higher gastric pH to
`
`and K. G. Wormsley (eds.) Stuttgart, 1981, p. 150.
`have high duodenal pH, or vice versa, among the young,
`
`23. J. D. Maxwell, A. Ferguson, and W. C. Watson. Digestion
`.
`4:345 (1971).
`
`healthy adults enrolled in this study. It should be noted,
`24. P. M. Christiansen. Scand. J. Gastro. 3:497 508 (1968).
`
`
`
`
`though, that in certain disease states where lumenal pH val­
`25. H. Ogata, N. Aoyagi, N. Kaniwa, A. Ejima, K. Suzuki, T.
`
`ues are far from the normal range of values, carryover pH
`
`
`
`Ishioka, M. Morishita, K. Ohta, Y. Takagishi, Y. Doi, and T.
`
`
`effects have been observed (e.g., Ref. 23).
`Ogura. J. Pharm. Dyn. 7:65&-664 (1984).
`
`26. R. McGill, J. Tukey, and W. A. Larsen. Am. Stat. 32:12 (1978).
`
`
`A trend toward differences in gastric pH due to gender
`
`
`27. P. J. Huber. Robust Statistics, Wiley-Interscience, New York,
`
`
`was reported by Dotevall ( 1 4), with the pH for males slightly
`1981.
`
`
`lower than the pH for females. Other studies either report no
`28. C. Chatfield.
`3rd
`The Analysis of Time Series An Introduction,
`
`
`
`significant difference in gastric pH due to gender (24) or
`ed., Chapman and Hall, New York, 1984.
`
`
`
`make no reference to gender-related differences. Often, the
`
`
`
`1985.
`
`number of female subjects was too small for statistically
`30. J. L. Devore. Probability
`and Statistics for Engineering and the
`
`
`
`
`meaningful comparison. In our study, no gender differences
`
`
`Sciences, Brooks/Cole, Monterey, Calif., 1982.
`II Manual, Abacus Concepts,
`
`in gastric or duodenal pH or in the intersubject or intra­
`31. Statview'"
`
`BrainPower, Inc., Cal­
`
`
`subject variability in pH were observed.
`
`abasas, Calif., 1988.
`
`11. A. V. Aynaciyan and J. R. Bingham. Gastroenterology 56:47&-
`
`29. Statworks'" Manual, Cricket Software Inc., Philadelphia, P