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`Pharmaceutical Research, Vol. 7, No. 7, 1990
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`Report
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`Upper Gastrointestinal (GI) pH in Young, Healthy Men
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`and Women
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`
`1 Lambros C. Dermentzoglou,
`1
`1
` Rosemary R. Berardi,
`Jennifer B. Dressman,
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`
`1 Stephen P. Schmaltz,
`2 Jeffrey L. Barnett,
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`3 and Kathleen M. Jarvenpaa
`2
`Tanya L. Russell,
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`•4
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`Received May 8, 1989; accepted January 15, 1990
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`The pH in the upper gastrointestinal tract of young, healthy men and women was measured in the
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`fasting state and after administration of a standard solid and liquid meal. Calibrated Heidelberg cap­
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`sules were used to record the pH continuously over the study period of approximately 6 hr. In the
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`fasted state, the median gastric pH was 1.7 and the median duodenal pH was 6.1. When the meal was
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`administered the gastric pH climbed briefly to a median peak value of 6. 7, then declined gradually back
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`to the fasted state value over a period of less than 2 hr. In contrast to the pH behavior in the stomach,
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`feeding a meal caused a reduction in the median duodenal pH to 5.4. In addition, there was consid­
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`erable fluctuation in the postprandial duodenal pH on an intrasubject basis. The pH in the duodenum
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`did not return to fasted state values within the 4-hr postprandial observation period. There was no
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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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`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.
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`KEY WORDS: gastric pH; duodenal pH; fasted state pH; fed state pH; young adults; gender effects;
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`carryover pH; food effects.
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`INTRODUCTION
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`tinuous monitoring under fasting and fed conditions in the
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`same group and at both gastric and duodenal locations. In
`Since small changes in the GI pH profile can affect dos­
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`particular, the pH in the mid to distal duodenum has re­
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`age form performance, drug dissolution, and drug absorption
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`ceived little attention. A further problem is that most of the
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`(l-5), it is important for the formulator to know the range of
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`meals studied were not designed to resemble the average
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`usual values for GI pH and how it varies under normal phys­
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`North American diet. Only Malagelada et al. (6,7), McCloy
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`iological conditions. There have been numerous previous
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`et al. (8), and Savarino et al. (9) have attempted to study pH
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`studies specifically designed to examine pH in the upper GI
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`response to ordinary solid/liquid meals. Moreover, the num­
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`tract (6-23). However, the experimental protocol (meals,
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`ber of subjects in most of the studies is relatively small, most
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`method of measurement, duration of monitoring period, fre­
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`of the studies used predominantly male subjects and there
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`quency of sampling, etc.) varied widely among these studies,
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`was usually little restriction on the subject age range.
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`making it difficult to compare the results obtained and to
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`In this article, we report data for fed and fasted GI pH
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`interpret them in terms of the pH to which a dosage form
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`in a total of 34 healthy, young subjects (24 subjects for the
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`would be exposed under normal dosing conditions. In addi­
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`gastric phase and 22 subjects for the duodenal phase). The
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`tion, in some of the studies, there was a wide range of sub­
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`data were obtained using a continuous monitoring device,
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`ject ages or a high mean subject age. This is an important
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`the Heidelberg capsule. Continuous recording of data al­
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`point since other studies have indicated that increasing age is
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`lowed us to better characterize peaks and fluctuations in pH
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`associated with changes in GI pH (24,25).
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`and to follow the functional form of the rate of return to
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`None of the previous studies have measured pH by con-
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`baseline after a meal. A standard solid/liquid meal was given
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`to assess the pH response that might be typical for the North
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`American diet. The study design also permitted the investi­
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`1 College of Pharmacy, University of Michigan, Ann Arbor, Mich­
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`gation of correlation between gastric pH values and duode­
`igan 48109-1065.
`2 Clinical Research Center, University of Michigan, Ann Arbor,
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`nal pH values within specific subjects. The information ob­
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`tained from these studies is intended to help identify situa­
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`Michigan 48109-1065.
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`tions in which drug bioavailability might vary as a result of
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`3 Department of Internal Medicine, University of Michigan, Ann
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`Arbor, Michigan 48109-1065.
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`pH changes associated with normal physiological function of
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`4 To whom correspondence should be addressed.
`the upper GI tract.
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`0724-8741/90/0700-0756$06.00/0 © 1990 Plenum Publishing Corporation 756
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`Upper GI pH in Young Adults
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`757
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`pH Measuring System
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`MATERIALS AND METHODS
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`Subject Selection
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`the subjects. Fasting pH in the body of the stomach_ was
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`recorded for 1 hr in all 24 subjects. Then a standard meal
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`consisting of 6 oz of hamburger, 2 slices of bread, 2 oz of
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`hash brown potatoes, 1 tbsp each of ketchup and mayon­
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`The study was conducted in the Clinical Research Cen­
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`naise, 1 oz each of tomato and lettuce and 8 oz of milk (for
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`ter of The University of Michigan Hospitals on an outpatient
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`a total of 1000 Kcal) was given. Subjects were required to
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`basis, with approval of the Institutional Review Board for
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`consume the meal within 30 min. Postprandial gastric pH
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`studies involving human subjects. All participants gave writ­
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`was monitored for 4 hr after completion of the meal, then the
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`ten informed consent. Thirty-four healthy volunteers (18 fe­
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`capsule was retrieved orally.
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`male, 16 male), with a mean age of 25 years (range, 21-35
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`Phase B. The participants fasted (with only water per­
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`years), participated in the study. Twelve subjects completed
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`mitted) for at least 12 hr before swallowing a tethered
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`both phases, twelve subjects completed only the gastric
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`Heidelberg capsule. Gastric pH was monitored until the cap­
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`phase, and ten subjects completed only the duodenal phase
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`sule emptied into the small intestine, an event marked by a
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`of the study. None of the participants had a history or any
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`rapid, unreversed elevation in pH accompanied by an in­
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`clinical or laboratory evidence of gastrointestinal disease.
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`crease in tether length. After the capsule emptied from the
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`The health status of each subject was confirmed by a general
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`stomach, it was allowed to travel approximately 10-15 cm
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`physical examination and routine screening of blood samples
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`farther (i.e., to the mid to distal region of the duodenum).
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`for renal and hepatic function. None were taking medica­
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`The position was fixed by taping the tether to the subject's
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`tions on a chronic basis. Smoking, alcohol, and all medica­
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`cheek. Tether length at this position ranged from 65 to 85
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`tions were discontinued for 3 days prior to and throughout
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`cm. The correspondence of this tethering procedure to the
`each study phase.
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`D3-D4 region of the duodenum was verified by fluoroscopy
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`in 12 subjects. Fasting pH in the duodenum was recorded for
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`1 hr in 12 subjects and 30 min in 10 subjects. Then a standard
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`meal identical to that administered in Phase A was given.
`Continuous determination of pH with time was accom­
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`Postprandial pH in the duodenum was monitored for 4 hr
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`plished using a radiotelemetric device, the Heidelberg cap­
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`after completion of the meal, then the capsule was retrieved
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`sule (10-12). The device consists of a battery-operated high­
`orally.
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`frequency radio transmitter and a pH electrode housed in a
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`nondigestible acrylic capsule 7 mm in diameter and 20 mm in
`Data Analysis and Statistical Considerations
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`length. The frequency of transmission changes with the pH
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`of the capsule's environment and can be calibrated using
`The pH measurements for the study were stored at 15-
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`standard buffer solutions. The subject wears an antenna
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`sec intervals using a program written in BASIC for the Apple
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`strapped around the waist to receive the radio signal, which
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`Ile computer. Data were divided into three periods (fasted,
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`is then converted back to pH and recorded continuously as
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`during the meal, and postprandial) for both the gastric phase
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`a function of time on an analogue recorder and digitally at
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`and the duodenal phase of the study. Data were collected for
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`15-sec intervals on an Apple Ile computer (Apple Computer
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`1 hr in the fasted state and for 4 hr in the postprandial state.
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`Co., Cupertino, CA).
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`Data were also collected during meal ingestion, a period
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`In vitro studies were conducted previously to confirm
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`which varied between 12 and 30 min.
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`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
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`study period (13). The capsule battery was activated with
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`displayed as box-whisker plots (26), which list the median
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`normal saline the morning of the study. Immediately prior to
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`and interquartile range for each subject or for pooled data
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`administration, the capsule unit was calibrated in pH 1 and 7
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`(see Fig. 1), or as frequency distributions. In all cases where
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`was teth­buffer solutions maintained at 37°C. The capsule
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`overall median values are reported, they are calculated from
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`ered using surgical thread (Supramid Extra 2-0, S. Jackson
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`the subjects' individual medians. Individual medians were
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`Inc., Alexandria, VA) to regulate capsule placement during
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`calculated based on all data points of a subject in each spec­
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`the study and to facilitate oral retrieval. At the end of each
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`ified phase. Interquartile ranges show the difference be­
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`study day, the capsule was recovered and its response to pH
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`tween the individual first and third quartiles. The frequency
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`1 and 7 buffers checked against the prestudy values. The
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`distribution plots show the percentage of the pooled data
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`response was required to be within 0.5 pH unit of the pre­
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`study values for results to be included in the data analysis.
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`Study Protocols
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`- Upper Extreme
`-
`3rd quartile
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`Phase A. The participants fasted (with only water per­
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`95,. confidence interya/
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`mitted) for at least 12 hr before swallowing a tethered
`-Median
`I
`ahout 11,o median
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`Heidelberg capsule. After the capsule had traveled approx­
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`imately 50 cm, its position was fixed by taping the tether
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`thread to the subject's cheek. Position in the body of the
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`stomach was indicated by a combination of tether length and
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`continuous recording of normal gastric pH (approximately
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`pH 3 or lower) and was verified by fluoroscopy in twelve of
`Fig. 1. Typical form of the box-whisker plot.
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`Interquartile
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`range
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`-- 1st quartile
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`

`758
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`Dressman et al.
`
`above or below specific pH values. The median absolute
`deviation (MAD) was used to describe variability. This pa­
`rameter is defined as the median of the absolute deviation
`from the individual medians and was calculated for each
`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
`tribution (27).
`For the construction of the 5-min interval box-whisker
`plots, each subject's data were divided into 5-min periods
`and the median of each successive period was computed.
`Each box in such a plot shows the between-subjects grand
`median for the 5-min interval. Since the meal period varied
`between 20 and 30 min, during the meal data were not in­
`cluded in the 5-min interval plots.
`Time-series and spectral analyses (28) were performed
`on fasting and postprandial data, smoothed by condensing
`into 5-min medians, to determine any temporal effects. To
`diagnose periodicity in the time domain, time-series analysis
`was initially performed. Wherever the results were ambigu­
`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.
`The two parameters (starting pH value and first-order rate
`constant for the rate of return of pH to the premeal value)
`were tested for normality and found to be normally distrib­
`uted. Subsequently, the mean value of each parameter was
`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
`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
`lyze the data since, regardless of transformation, the pH
`distributions deviated considerably from normality, as deter­
`mined by the Kolmogorov-Smirnov normality test (29). Spe­
`cifically, the data from 50% of the subjects in the fasted
`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).
`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
`sum (Mann-Whitney l.1) test (30). Spearman's rank correla­
`tion coefficient (31) for the medians was calculated to deter­
`mine whether there was a carryover effect between the gas­
`tric and the duodenal pH values in each of the phases of data
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`collection, i.e., fasted state, during the meal and postpran­
`dial.
`For all tests, a P value <0.05 was considered signifi­
`cant. The statistical software packages Midas, Statview, and
`BMDP were used for the analysis of all data.
`
`RESULTS
`
`Typical pH Profiles
`
`Figure 2 shows typical gastric and duodenal pH profiles.
`In the fasted state, there were periods during which gastric
`pH remained steady, while at other times there were fluctu­
`ations during which the pH was elevated to higher values.
`This kind of behavior was observed to a varying degree in
`almost all gastric preprandial profiles, usually for a period of
`about 1 to 15 min (average duration, 7 ± 6 min). High pH
`values were attained while the meal was being ingested.
`Postprandially, the gastric pH decreased gradually over time
`and, in most cases, returned to the fasted state levels within
`the 4-hr period of monitoring. In the duodenum the pH re-
`
`7-,-----:M-:---- -- ---------
`
`-- -- �
`A
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`6
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`5
`
`4
`
`:c
`
`Cl
`3
`
`2
`
`-'
`o--i----.-----.----.-------.----�
`4
`0
`-1
`3
`2
`Tim• (hours)
`
`:c
`
`Cl
`
`2
`
`B
`O-t---- ---. --- � ---- ,-- --- .- -----1
`-1
`0
`3
`4
`
`2
`Tim• (hours)
`Fig. 2. Typical pH profiles in gastric (upper panel) and duodenal
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`(lower panel) phases of the study for subject J. L. Meal administra­
`tion is marked by M.
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`

`

`Upper GI pH in Young Adults
`
`7S9
`
`mained relatively constant in the fasted state. In contrast,
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`wide fluctuations in duodenal pH were observed during the
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`postprandial period. The usual duodenal pH appeared to be
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`lower in the postprandial than in the fasting state, and in
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`most cases there was no return to the fasted state pattern
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`within the 4-hr postprandial observation period.
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`Gastric Data
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`lime (minuf•$)
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`The overall median fasting pH was 1. 7, with an inter­
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`quartile range of pH 1.4-2.1. During the meal, the pH in­
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`creased to a median value of 5.0 with an interquartile range
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`of pH 4.3-5.4. The peak value was 6.7 (6.4-7.0). Figure 3
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`shows the pH frequency distribution in the fasted state and
`o...L��-�-�-�-�-�-��-�---r
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`
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`during the ingestion of the meal. Figure 4 shows the box­
`-30 0 30 60 90 120 150 180 210 240
`
`
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`whisker plot for the postprandial period in 5-min intervals
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`
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`using data pooled from all subjects, beginning at the end of
`inter­Fig. 4. Box-whisker plots for pooled data from three 15-min
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`the meal. The first three boxes correspond to the 15-, 30-,
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`vals prior to meal administration and at 5-min intervals postprandi­
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`ally for the gastric phase of the study.
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`and 45-min intervals in the fasted state. Values of pH re­
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`corded during the meal were not included, as the period of
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`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
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`gastric postprandial pH data was to decline gradually from a
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`the overall median pH was 6.3 (interquartile range of 6.0-
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`near-neutral peak pH. The postprandial pH data were sub­
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`6. 7). Time-series analysis showed that duodenal postpran­
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`
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`sequently fitted to a two-parameter exponential equation,
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`dial data did not exhibit any periodicity or other temporal
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`
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`effects but, rather, that pH fluctuated randomly around a
`pH = 4.13 . e-o.oos,
`(1)
`
`
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`grand median value of 5.4. Individual medians varied from
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`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
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`
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`of pH 3.1 to a maximum of pH 6.7 (overall median values).
`
`
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`2 postprandially. The means, standard deviations, medians,
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`Comparison of duodenal pH in the three phases showed that
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`and ranges are shown.
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`pH was highest during ingestion of the meal and lowest in the
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`postprandial period. Differences between phases reached
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`significance in each case.
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`The overall median fasting pH was determined to be 6.1,
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`Duodenal Data
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`90
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`80
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`70
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`60
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`50
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`40
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`30
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`20
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`10
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`Correlation Between Gastric and Duodenal pH
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`Correlation coefficients were below the critical value for
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`significance between fasted gastric and duodenal pH and
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`between postprandial gastric and duodenal pH.
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`Variability
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`The ratio of highest to lowest median absolute deviation
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`(MAD) was 17: 1 for the gastric fasted state pH, indicating
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`considerable differences in pH variability between subjects.
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`Variability in gastric and duodenal pH during the meal also
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`showed large differences between subjects, with the ratio of
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`largest to smallest being 12:1 for the gastric and 11:1 for the
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`duodenal study. In contrast, the range of variability for the
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`postprandial phases was relatively small, with ratios of 5:1
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`and 7:2 for the gastric and duodenal studies, respectively.
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`Likewise, little intersubject variability was observed for the
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`fasting phase of the duodenal study, where the MAD ratio
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`Table I. Time to Return to Specific pH Values, After Completion of
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`the Standard Meal (Minutes)
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`2 3 4 5 6 7 8
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`Mean± SD
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`Median Range
`
`pH5
`pH
`Fig. 3. Frequency distribution plots for pooled gastric pH in the
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`
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`pH4
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`fasted state (A) and during ingestion of the meal (B). The percentage
`pH3
`
`
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`of data falling below a given pH value can be obtained by reading the
`pH2
`
`
`percentile corresponding to the pH of interest.
`
`11 ± 10
`28 ± 24
`56 ± 41
`107 ± 70
`
`8
`14
`45
`96
`
`2-34
`4-74
`2-158
`8-240
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`

`760
`
`Dressman et al.
`
`was 4: 1. With regard to intrasubject variability, there was a
`higher variation in the gastric phase during the meal and in
`the duodenal postprandial phase, relative to the other
`phases.
`
`Gender Effects
`
`With regard to gender effects, data were not signifi­
`cantly different between men and women in any of the
`phases of the study.
`
`DISCUSSION
`
`Fasting gastric pH has been well studied (6,7,9,14-19),
`with little variation among the results obtained. The gener­
`ally accepted value for fasting gastric pH is approximately
`pH 2. We observed a median fasted gastric pH of pH 1.7,
`with a considerable degree of intersubject variation. The fre­
`quency distribution in Fig. 3 indicates that the fasted-state
`gastric pH is below pH 2 68% of the time and below pH 3
`90% of the time. In young healthy volunteers, pH above 4 is
`evident about 6% of the time, while pH above 6 is very rare
`in the fasted state.
`During the 1-hr observation period in the fasted state,
`episodes of elevated pH were recorded in the majority of
`subjects. It is postulated that this may be due to contact of
`the measuring device with the stomach wall. Alternatively,
`there may be a genuine elevation of the lumenal pH. The
`latter would explain why some "tubeless gastric pH analy­
`sis" and single-point aspiration studies (20) reported a higher
`incidence of raised gastric pH than multipoint aspiration or
`continuous monitoring study designs.
`Postprandial gastric pH (6,7,9,17-19) is not as well char­
`acterized as fasted-state data. The only groups in this series
`which studied pH changes after a normal solid meal were
`Savarino et al. (9) and Malagelada et al. (6,7). The pH re­
`sponse during and immediately after the meal is ingested is
`particularly poorly characterized because data were either
`collected by pooling aspirates or reported only at certain
`intervals. These methods tend to obscure important data
`such as peak pH value and time of peak pH. Return to fast­
`ing pH in the studies listed generally occurred within 60 min
`after the meal. In our study, ingestion of the meal resulted in
`a substantial elevation of the gastric pH. The median peak
`pH following ingestion of the hamburger, hashed brown po­
`tatoes, and milk meal was 6.7, with an interquartile range of
`6.4 to 7.0. This can most likely be attributed to the buffering
`effect of the fluid (in this case, milk) and food ingested.
`When the meal was homogenized, its pH was 5.72. Other
`meals with lower-pH fluids such as coffee, cola drinks, fruit
`juices, etc., may not buffer the gastric pH to as high a peak
`pH. Malagelada and co-workers' (6,7) studies used water as
`the fluid portion of the meal, while Savarino et al. did not
`describe the meal contents. Some of the fluid-only meals
`consisted of chocolate milk, which contains alkaloids such
`as caffeine. These alkaloids may augment the normal nutri­
`ent stimulation of gastric acid secretion.
`During meal ingestion, the pH was above pH 4 73% of
`the time (Fig. 3), above pH 5 45% of the time and above pH
`6 20% of the time. The time taken to ingest the meal was
`between 12 and 30 min for all subjects. The peak pH usually
`occurred within the first 5 min of eating. These results sug-
`
`gest that it would be unwise to recommend administration
`with meals for formulations/drugs which require acidic pH
`for rapid release. Further, enteric-coated preparations may
`partially release drug in the stomach if ingested during meal
`intake. Depending on their composition, other meals may
`result in a lower peak pH, but the prescriber must guard
`against worst-case pH conditions.
`After the meal was completed, the pH gradually de­
`clined until fasted-state pH was reestablished. Decline in pH
`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
`quickly falls back below pH 5 and then gradually declines
`back to fasted state values over a period of less than 2 hr.
`The fact that we observed a somewhat longer time for res­
`toration of the fasting state pH (-120 min, versus 60 min in
`most reported studies) is probably due partly to the large
`meal size (long emptying time) and partly to the high buffer
`capacity of the meal. There was considerable subject-to­
`subject variation in the rate of return to premeal values. In
`most people, though, medications administered 2 hr or more
`after meals should encounter gastric pH conditions similar to
`the fasted state. Enteric-coated dosage forms with a disso­
`lution pH of 5 or greater could be safely administered 20 min
`after meal intake is complete. These probably represent
`maximum times as most other meals would be smaller and/or
`have lower buffer capacity.
`Fasting duodenal pH has been most extensively mea­
`sured in the duodenal bulb (6,8,15,17-19,21). The wide vari­
`ation in mean pH values reported may be due to wide tem­
`poral and positional fluctuation in pH in this area of the
`duodenum, which makes it difficult to determine an accurate
`mean value (22).
`There have been only three studies which investigated
`pH in the mid to distal region of the duodenum. Of these
`three, two (6,15) used older subjects, with ages ranging up to
`63 and 67, respectively. Unlike the stomach, the fasted mid
`to distal duodenum appears to be very stable with respect to
`pH. This was illustrated by the low MAD values in this
`phase of the study. The median pH of 6.1 (interquartile range
`of 5.8 to 6.5) was similar to previously reported results for
`the distal duodenum. Figure 5 indicates that the pH in the
`fasted state is above pH 5 more than 90% of the time but
`rarely exceeds pH 7.
`There are only two studies which have reported values
`for postprandial pH in the mid to distal duodenum. Of these
`two, Ovesen et al. 's (18) used a liquid meal rather than a
`standard solid meal. The other (6) included older subjects
`and reported pH of pooled intestinal aspirates rather than
`using a continuous monitoring device. Pooling samples over
`collection intervals of several minutes makes it difficult to
`observe the fluctuations in duodenal pH which occur in the
`fed state (22). In contrast to the gastric results, the pH at mid
`to distal duodenum was observed to be lower postprandially
`than in the fasting state. Furthermore, in contrast to the
`duodenal bulb region, the low pH appears to be maintained
`throughout an extended observation period.
`Upon ingestion of the meal, a brief period of elevated
`duodenal pH was often observed. This can be attributed to
`the cephalic phase of pancreatic bicarbonate secretion (13).
`
`Bausch Health Ireland Exhibit 2032, Page 5 of 6
`Mylan v. Bausch Health Ireland - IPR2022-00722
`
`

`

`Upper GI pH in Young Adults
`
`761
`
`9 0
`
`8 0
`
`7 0
`
`6 0
`
`5 0
`
`4 0
`
`3 0
`
`2 0
`
`1 0
`
`2 3 4 5 6 7 8
`
`pH
`
`Fig. 5. Frequency distribution plots for pooled duodenal pH during
`ingestion of the meal (A) , in the fasted state (B) , and in the post­
`prandial state (C) .
`
`The pH in the postprandial phase in the duodenum is con­
`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
`fasted state. The equivalent numbers for time spent below
`pH 6 are 80 and 38%, respectively. Drugs for which the pH
`of half-maximal absorption lies in the pH 5 to 7 range may
`therefore be absorbed at different rates if given in the fed
`state as opposed to the fasted state. Formulations with pH­
`sensitive release profiles may also be expected to perform
`differently under fasted- versus fed-state conditions.
`During and following the meal, there were randomly
`spaced fluctuations in duodenal pH. These can be explained
`by the periodic emptying of chyme from the stomach, fol­
`lowed by reneutralization with pancreatic bicarbonate.
`Overall, the pH in the postprandial phase of the duodenal
`study appears to be somewhat lower and much more vari­
`able than the pH observed in the fasting state. The fluctua­
`tions in pH have been observed previously in the distal du­
`odenum when continuous monitoring was employed (18).
`There was no trend for those with higher gastric pH to
`have high duodenal pH, or vice versa, among the young,
`healthy adults enrolled in this study. It should be noted,
`though, that in certain disease states where lumenal pH val­
`ues are far from the normal range of values, carryover pH
`effects have been observed (e.g., Ref. 23).
`A trend toward differences in gastric pH due to gender
`was reported by Dotevall (14), with the pH for males slightly
`lower than the pH for females. Other studies either report no
`significant difference in gastric pH due to gender (24) or
`make no reference to gender-related differences. Often, the
`number of female subjects was too small for statistically
`meaningful comparison. In our study, no gender differences
`in gastric or duodenal pH or in the intersubject or intra­
`subject variability in pH were observed.
`
`ACKNOWLEDGMENTS
`
`This work was supported by MO l -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.
`
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