Journal of Pharmaceutical Sciences 105 (2016) 476e483

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Review

Literature Review of Gastrointestinal Physiology in the Elderly, in

Pediatric Patients, and in Patients with Gastrointestinal Diseases
Jane P. F. Bai 1, *, Gilbert J. Burckart 1, Andrew E. Mulberg 2
1
Office of Clinical Pharmacology, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland 20993
2
Division of Gastroenterology and Inborn Error Products, Office of Drug Evaluation III, Center for Drug Evaluation and Research, US Food and Drug
Administration, Silver Spring, Maryland 20993

a r t i c l e i n f o a b s t r a c t

Article history: Oral bioavailability studies during the development of new medical entities or generic drugs are typically
Received 28 June 2015 performed in healthy volunteers. Approved drug products are, however, used by patients with diverse
Revised 16 September 2015 disease backgrounds, and by pediatric and elderly patients. To provide the knowledge base for assessing
Accepted 30 September 2015
the potential effects of age or co-morbidity on the in vivo performance of an orally absorbed, systemically
Available online 5 November 2015
active drug product, the literature regarding the gastrointestinal (GI) physiological characteristics (pH,
permeability, and transit time) in children, in the elderly, and in patients with GI diseases (irritable bowel
Keywords:
syndrome, ulcerative colitis, and Crohn's disease) is reviewed herein, with the knowledge gaps
paracellular transport
passive transport disease effects
highlighted.
pediatric © 2016 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.
gastrointestinal transit
permeabiltiy
elderly
CYP enzymes
transporters
metabolism
solubility

Introduction The first-in-man study and early clinical pharmacology studies

Oral formulations developed for achieving the desired phar-
macokinetic characteristics and clinical efficacy of individual
drugs include immediate release (IR), extended release, modified
release, and delayed release formulations. When designing
an oral drug product, regardless of a new chemical entity or a
generic drug, many factors would be considered, including its
absorption, disposition, metabolism, and elimination profile, its
stability in the stomach, its physicochemical properties (pKa,
lipophilicity, solubility), its dose, the local site of delivery, and
gastrointestinal (GI) physiology. GI physiology plays an impor-
tant role in affecting the in vivo performance of a drug product
and in the extent of its oral pharmacokinetic variability in its
target disease population.
The views expressed in this article do not represent the views of the United States
Food and Drug Administration.
* Correspondence to: Jane P. F. Bai (Telephone: þ301-796-2473).
E-mail address: jane.bai@fda.hhs.gov (J. P. F. Bai).
are in general conducted in healthy adults; as are the bioequiva-
lence studies for generic drugs. To translate and predict the
bioavailability results from healthy volunteers to the pediatric pa-
tients, to the elderly patients, and to the disease population,
understanding of the GI physiological characteristics across all age
groups and across subpopulations with local GI diseases is impor-
tant. Notably, the intestinal mucosal surface area increases from
approximately 3320 cm2 in infants to 17,700 cm2 in adults,1 Adults
aged 65 and older constituted 12.9% of the US population in 2009
and will constitute approximately 19% of the US population
by 2030.2 GI physiological characteristics with respect to drug
absorption may differ among healthy adults, adult patients, elderly
patients, pediatric patients, and patients with GI diseases.
Conceivably, the interaction between individual patients' GI phys-
iological profiles and the formulation characteristics of a drug
product could cause significant inter-subject differences in the
in vivo performance (AUC and Cmax) of an active pharmaceutical
ingredient (API).
In addition to age, GI diseases are another factor that could
potentially impact in vivo performance of an API as a result of

http://dx.doi.org/10.1002/jps.24696
0022-3549/© 2016 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.
 J.P.F. Bai et al. / Journal of Pharmaceutical Sciences 105 (2016) 476e483
physiological changes. Among the non-cancerous GI diseases, ir-
ritable bowel syndrome (IBS) and inflammatory bowel disease
(IBD) are very common. IBS affects 25-45 million people in the US
and 9%-14% of populations worldwide3; IBD affects 1.4 million
people in the US and 396 per 100,000 persons worldwide.4
Considering the sizes of elderly and pediatric populations and
the prevalence of IBS and IBD, we reviewed the literature for GI
physiology and function in these patient populations and
compared their GI characteristics. We reviewed herein the liter-
ature regarding the factors that could affect oral bioavailability or
local delivery of an oral product, and highlighted the emerging
knowledge gaps.
Factors Controlling Oral Absorption
The form of an API (i.e., whether a crystalline or amorphous
solid state or a salt) as well as the specific formulation used could
influence its in vivo release, and consequently its rate and extent of
absorption. Additionally, GI physiology also significantly affects oral
bioavailability.5-7 Oral absorption of a drug is determined by its
intestinal membrane permeability (including paracellular perme-
ability, passive transcellular permeability, and/or carrier-mediated
transport); luminal concentration or maximal luminal concentra-
tion (solubility) of the non-ionized form; available GI absorption
surface area; and GI transit time.8 Three of these parametersd
permeability, luminal concentration of the dissolved, un-ionized
drug after release from the formulation, and total transit time of the
formulated drugdcan be used to mathematically calculate oral
absorption of a drug as follows:
 
∬ Jdsdt ¼ ∬ Jpassive þ Jcarriermediated dsdt
¼ ∬ ðPw C þ Pcarriermediated CÞdsdt
Equation (1) describes the amount of drug absorbed, where J is
flux per unit surface area and unit time and comprises passive and
carrier-mediated components; Pw is apparent passive permeability;
Pcarrier-mediated is apparent carrier-mediated permeability; C is the
luminal concentration, assuming a sink condition on the other side
of the membrane; s is the absorption surface area; and t is transit
time. If assuming only the ionized form is absorbed via the carrier-
mediated route, the above equation applies to a zwitterion drug
and a strong acid drug that is almost completely ionized beyond the
duodenum. Drug molecules are a weak acid or base. For a weaker
Ka C
acid with a single pKa value, Pcarrier­A  ½A ¼ Pcarrier­A *Ka þ½Hþ,
so the apparent Pcarrier-A is defined as Pcarrier-A * Ka/(Kaþ[Hþ]) and
used in Equation (1) as a general form with the total concentration,
C. Pw is defined as DK h
, with D as the diffusion coefficient; K as the
partition coefficient, and h as the membrane thickness.
Passive flux is attributed mainly to transmembrane permeation
and, to a small extent, paracellular transport. The luminal pH profile
along the GI tract and the pKa values of the drug are factors of its
un-ionized concentration in the lumen, and thus, its passive flux, as
only the un-ionized form can permeate through intestinal epithe-
lium. For a drug primarily absorbed via a carrier-mediated process,
once it is dissolved in intestinal fluid, the fraction absorbed is
controlled by the level of transporter expression along the intestine
and its binding affinity to the transporter. Intestinal epithelium is
comprised of villi and microvilli, especially prominent in the small
intestine, which increases the surface area available for drug ab-
sorption beyond the geometric surface area contributed by intes-
tinal radius and length. Therefore, a specific formulation design
rendering a longer resident time, particularly at the site where its
absorption takes place, would be used to achieve a higher extent of
absorption.9,10
477
The factors highlighted above affect in vivo performance of a
drug product and, hence, also play a key role in affecting in vivo oral
bioavailability and efficacy. Individual physiological and disease
factors, in addition to aging and developmental factors, impact
permeability and transit time and, ultimately, in vivo performance
of drug products. These factors and their associated impacts are
discussed below.
GI Factors Affecting In Vivo Performance of Drug Products
The reviews below focus on important GI physiological factors
that will provide the basis for future physiologically based ab-
sorption modeling case studies evaluating the impacts of age,
developmental changes, and GI diseases on the in vivo performance
of drug products.
GI Dimensions and Capacity
The volume of gastric fluid is normally small ([averaging 28 mL
and ranging from 18 to 54 mL])7; or [ranging from 20 to 100 mL] in
healthy adults,11 but gastric capacity can range from 2000 to 3000
mL to accommodate food ingestion. Gastric capacities increase
with development: neonates (10-100 mL); infants and toddlers
(90-500 mL); older children (750-960 mL); and adolescents (1500
mL).7 Intestinal dimensions increase from 275 cm in length and
1.9 cm in diameter at birth to 600-800 cm in length and 4.5 cm in
diameter in adults.1 Among children, intestinal lengths increase
with age: neonates (275 cm), infants and toddlers (380 cm), and
older children (450 cm).7 As developmental changes are multi-
faceted, singular consideration of absorption surface area in
calculating pediatric doses is likely inadequate without consid-
ering ontogenic changes in enzymes, transporters, transit time,
(1) and luminal pH.
GI Transit
Once swallowed, an oral dosage form disintegrates in the
stomach or intestine and drug molecules are dissolved and absor-
bed. Hence, Tmax is highly influenced by gastric emptying, espe-
cially for IR products, and the bioavailability of acidic drugs that are
absorbed primarily in the stomach. Acid-labile drugs that are pro-
tected by an enteric or pH-dependent coating dissolve at a pH > 5
only in the duodenum and further along the intestine; therefore,
these drugs are subject to the impact of gastric emptying as well.
Moreover, upon gastric emptying, oral solid dosage forms (modi-
fied-release, delayed-release, extended release) that do not disin-
tegrate and dissolve in the stomach could be subject to the
influence of aging and GI diseases on their transit in the GI tract;
consequently, so are their delivery profiles.8
Impact of Age
Total transit times and transit profiles are similar between
children aged 8-14 years12 and adults aged 18-65 years.13 Cross-
study comparisons of total GI transit or orocecal transit across
various age groups of healthy subjects including children (neonates
included), adults, and the elderly are summarized in Table 1.12-18
Upon further examining the results reported by Brogna et al.,14
though the elderly adults (on average, 75 years of age) and
younger adults (on average, 30 years old) had similar total GI transit
times as shown in Table 1, they had a significantly slower gastric
emptying of radiopaque markers (2  5 mm2) taken with a meal,
than younger adults. From the group of children averaging 5.5 years
old (2 months to 12 years old) studied by Corazziari et al.15
(Table 1), further analysis by dividing the children into two
different age groups of 2-3 years old group and 3-12 years old group
478 J.P.F. Bai et al. / Journal of Pharmaceutical Sciences 105 (2016) 476e483

Table 1
Comparisons of Total GI Transit and Oracecal Transit Across Age Groups of Healthy Subjects and Across GI Diseases

Transit Time Healthy Children Healthy Adults Healthy Elderly IBS UC CD Markers, Devices Used

Total GI transit Median: 26.1 h Median: 26.6 h (9.2-129 h) Radio-transmitting

(age: 8-14 years)12
25 ± 3.7 h (mean
age: 5.5 years)15
Orocecal transit Median: 3.1 h (1.3-6.1 h)
postnatal age: 6-37 days17
(age: 18-65 years)13 capsule (24  7 mm2)12,13
69 ± 5 h (mean age: 76 ± 6 h (mean age: Polyethylene
30 years)14 75 years)14 radiopaque (5 mm)15
1.6 h (95% CI 1.3-1.9 h) 2.52 (95% CI: 2.04 ± 0.86 h 2.32 ± 0.83 h Lactulose16,18
(mean age 31 years)16 2.08-2.95 h) (mean (mean age: 45 years)18 (mean age:
age: 81 years)16 46 years)18
1.51 ± 0.51 h (mean age: Liquid marker,
45 years)18 preterm infants17

Note: The data above are mean ± SD.

revealed no difference in the total GI transit time between these
two groups. According to the results of a study of gastric, small
intestinal and coloniic transit times in younger adults (20-30 years
old) and middle-aged adults (38-53 years old),19 we concluded, by
summing up individual average transit times for each group, that
total GI transit time was shorter in younger adults (20-30 years old)
compared with middle-aged adults (38-53 years old) for both liquid
and colloidal markers taken with a meal. Because of the lack of
numerical data, this study is not included in Table 1.
Cross-study comparisons of gastric emptying, small intestinal
transit and colonic transit across various age strata, including
neonates, infants and toddlers, older children, adolescents, adults,
and the elderly are summarized in Table 2.13,17,19-25 Children have
drastic growth changes compared with adults. Depending on the
age range included in a study, the reported outcome could differ
from study to study. Therefore, when referencing the results of
pediatric studies, it is important to pay attention to the differences
in age group. For example, cross-study comparisons shown in
Table 2 revealed that children aged 0-2 years had slower gastric
empting than older children and adolescents aged 2-16 years,22 but
had similar gastric emptying as the older children aged 2-5 years.23
When referencing the GI transit studies, the type of markers used

Table 2
Comparisons of Transit in Various Gastrointestinal Regions Across Age Groups of Healthy Subjects and Across GI Diseases

Transit Time Healthy Children Healthy Adults Healthy Elderly IBS UC CD Markers, Devices Used

Gastric Median: 1 h (0.5-3 h) Mean: 1.36 h (0.53-1.96 h) Mean: 1.37 h (1.07-1.85 h) Liquid marker, preterm
emptying postnatal age: 6-37 (liquid marker); mean: (liquid marker); 2.07 h infants17
time days17 2.01 h (1.03-2.73 h) (Solid (1.32-3.03 h) (solid
colloid marker) (age: 20-53 marker) (age: 74-85
years)19 years)21
55 ± 29% remained in Liquid and colloid markers19,21
stomach after 1 h (age:
0-2 years)22
31 ± 19% remained in Colloid marker in children
stomach after 1 h (age: without GERD22,23
2-16 years)22
The half-emptying time:
0.65 ± 0.32 h (age: 0-2
years); 0.67 ± 0.27 h (age
2-5 years)23
Median 1.1 h (0.2-2.3 h) Median 0.9 h (0-4.8 h) (age: 0.57 ± 0.66 h 1.05 ± 1.05 h Radio-transmitting capsule
(age: 8-14 years)12 18-65 years)13 (mean age: (age: 35.8 ± (24  7 mm2)12,13,24
35 years)20 14.23 years)24
0.12-2.12 h; median: 0.96 h Capsule (13  26 mm2)20
(age:25-61 yrs)25
0.85 ± 0.81 h (mean age: 35 Magnet tracking system (6  25
yrs)20 mm2) and video capsule (11 
26 mm2)25
Small intestinal Mean: 3.95 h (1. 52-6.6 h) Mean: 4.95 h (2.21-8 h) Liquid and colloid markers with
transit time (liquid marker); mean: 3.63 h (liquid marker); 4.77 h a meal19
(2.4-5.89 h) (solid colloid (2.53-8.13 h) (solid
marker) (age: 20-53 years)19 marker) (age: 74-85
years)21
Liquid and colloid markers with
a meal21
Median: 7.5 h (5.1e9.2 h) Median: 8.0 h (age: 18-65 2.43 ± 0.66 h 8.9 ± 5.9 h Radio-transmitting capsule
(age: 8e14 years)12 years)13 (mean age: (age: 35.8 ± (24  7 mm2)12,13,24
35 years)20 14.23 years)24
2.21 ± 0.91 h (mean age: 33 Capsule (13 mm  26 mm)20
years)20
Median: 4.58 h (3.48-6.33 h) Magnet tracking system (6  25
(age: 25-61 years)25 mm2) and video capsule (11 
26 mm2)25
Colon Median: 17.5 h (6.2-54.7 h) Median: 17.5 h (age: 18-65 Mean: 66 h (29-98 h)* Radio-transmitting capsule
(age: 8-14 years)12 years)13 (age: 74-85 years)21 (24  7 mm2)12,13,24
Mean: 39 h (14-75 h) (age: Liquid and colloid markers19,21
20-53 years)19

Note: *, One subject had the colon transit time of >97.7 h; the 98 h was used in calculating the data. The data above are mean ± SD.
 J.P.F. Bai et al. / Journal of Pharmaceutical Sciences 105 (2016) 476e483
could affect the outcome. Interestingly, both magnet pill and
capsule produced similar results.25
Impact of GI Diseases
Irritable bowel syndrome is a disorder of the colon with varying
subtypes including constipation-predominant (IBS-C), diarrhea-
predominant (IBS-D), and a mixed type with both constipation
and diarrhea.26 Although the etiology of IBS is unknown, infection
and inflammation along with a cytokine imbalance has been re-
ported.27 IBD includes ulcerative colitis and Crohn's disease. Results
of small intestinal and colonic transit studies in IBS, UC, and Crohn's
disease patients with signal-transmitting capsule or a radiopaque
marker are highlighted with Table 2 for reference.13,17,19-25 In
addition to the studies summarized in Table 2, there are other
studies worthy of discussion because the clinical details revealed by
individual studies could be relevant for designing local acting drug
products. They are highlighted below. No significant difference was
noted in either fasted gastric emptying time or small intestinal
transit time between healthy adults and IBS patients, if IBS subtypes
were not considered.20 IBS patients, however, had longer colonic
transit times than normal healthy adults.28 IBS-C had prolonged
gastric emptying and three times longer colonic transit than IBS-D
or a mixed type.28 A cross-study comparison revealed that the
constipation subtype had an approximately 1.5-fold longer colonic
transit time than normal.7,28 Immediately after a meal, ileocolonic
transit was quicker in IBS-D than in healthy subjects, whereas
colonic transit was much longer in IBS-C.29 Chronic constipation
also prolonged total GI transit time in children.15 Patients with
UC or CD had slightly longer orocecal transit than healthy coun-
terparts.18 Crohn's disease patients with ileo-cecal resection had
faster small intestinal transit times than healthy controls.30 The
bioavailability of urea in a colon-targeted release formulation was
slightly higher in Crohn's disease patients than in healthy controls,
and Crohn's disease did not affect transit of the colon-targeted
formulation.31 Ulcerative colitis decreased contractility, but
increased low-amplitude propagating contractions.32 Patients with
Celiac disease caused by immune reactions to gluten in food, had
slower small intestinal transit than healthy controls.33
Summary
Results of GI transit studies are usually highly variable because:
(1) depending upon the study, human subjects swallow tracing
markers at varying points in the four phases of a fasting gastric
emptying cycle, including the quiescent phase and the active
emptying phase, and (2) study design and demographic character-
istics of study populations vary. Viscosity of the medium in which
markers are dispersed; the physical form of a marker, whether solid,
liquid, or colloid; and the dimension and size of solid markers all
could contribute to variability in gastric emptying. Age affects total
gastric emptying and intestinal motility. Total GI transit times of
small solids are much shorter in children than in adults and the
elderly. The elderly have a slightly longer orocecal (mouth to cae-
cum) transit, but a much longer colonic transit time, than healthy
adults. For oral formulations that are designed to disintegrate in the
distal intestine, their transit in the proximal GI tract could be derived
from the studies using radio-transmitting capsules. On the other
hand, liquid and small solid markers could be useful for assessing the
GI transit of oral solution or other formulations that disintegrate into
small pellets in the stomach or the duodenum.
pH
We reviewed and compared pH profiles along the Gl tract from
birth to old age and between healthy subjects and those with
common colonic diseases.
479
Impact of Age
Cross-study comparisons reveal that the fasting pH profile along
the GI tract of healthy adults follows: pH 1-3.7, stomach; pH 5-7.4,
duodenum; pH 5.5-7.7, jejunum; pH 6.6-7.9, ileum; pH 4.7-6.8,
caecum; 4.6-6.8, ascending colon; pH 5.5-7.4, descending colon;
and pH 5.3-7.4, rectum (Table 3).7,20,30,34-37 Healthy elderly men
and women averaging 71 years of age had a statistically signifi-
cantly lower gastric pH (~0.4 unit lower), but a higher duodenal pH
(~0.4 units higher), than healthy younger controls averaging 49
years of age.38
Whether Helicobacter pylori infection affects gastric pH has been
studied. Gastric acid secretion remained unchanged in H. pylori
negative patients, but decreased in H. pylori positive patients.39 The
decrease in gastric acid secretion was attributed to fundic gastric
atrophy and inflammatory cytokines. Reports differ overall
regarding whether aging impacts gastric pH. Confounding factors
such as contracting GI diseases early in life must be considered
when examining the effect of aging on gastric acid secretion. For
example, studying pH in elderly patients should factor in previous
H. pylori infection. GI bacterial overgrowth in the elderly has been
suggested.40 It is, however, not known whether there is a linkage
between luminal pH and bacterial growth.
Neonates have a higher gastric pH, ranging between 6 to 7 from
20 to 29 days after birth; 20 to 30 months after birth, gastric pH
lowers to 1-2.7 Gastric pH values are similar among infants, tod-
dlers, older children, and adults. Children, adolescents, and adults
have similar duodenal, jejunal, and colonic pH, except children and
adolescents have slightly lower caecal pH.7
Impact of GI Diseases
Inflammatory bowel disease does not change gastric or small
intestinal pH, but tends to decrease colonic pH (Table 3).37 Con-
flicting results are reported regarding whether patients with
Crohn's disease have a lower pH in the colon than healthy sub-
jects35-37 However, for both ulcerative colitis and Crohn's disease,
active disease seems to cause lower pH compared to inactive dis-
ease.36 Crohn's disease patients with ileo-cecal resection had a
cecal pH 0.9 unit higher than controls.30 During the fasted state, in
healthy controls and IBS patients, no difference was observed in pH
along the small intestine.20
Passive Permeability
Diarrhea predominant irritable bowel syndrome increased the
small intestinal and colonic permeability of mannitol and lactulose,
whereas ulcerative colitis increased colonic permeability only.41
IBS-D increase intestinal passive permeability,42,43 but non-post-
infectious IBS-D seemed to show a higher increase than post-
infectious IBS-D.44 Using 51Cr-EDTA and urine collected from
post-infectious and non-post-infectious IBS patients, both the small
and large intestine showed the same rank order of permeability
characteristics: non-post-infectious IBS > post-infectious > con-
trol.44 In IBS patients without differentiating IBS-D, IBS-C, or
infection, no increase in permeability was observed using urinary
secretion of sucralose, sucrose, mannitol, and lactulose.45 However,
another study that did not differentiate diarrhea, constipation, or
infection reported that IBS patients had higher paracellular
permeation than healthy controls and their intestinal supernatant
also increased paracellular permeation in the Caco-2 monolayer.46
Although how IBS subtypes affect intestinal permeability is
controversial, one common observation is that the intestines of IBS
patients have higher permeability than those of healthy controls.
Controversial results have also been reported regarding
permeability for Crohn's disease and ulcerative colitis. Crohn's
disease increased oral bioavailability of diethylene triamine
480 J.P.F. Bai et al. / Journal of Pharmaceutical Sciences 105 (2016) 476e483

Table 3
Cross-Study Comparisons of Gastrointestinal pH Profiles Across Populations

GI Segments Populations

Children (Healthy) Adults (Healthy) Elderly (Healthy) IBS Patients UC Patients CD Patients
7 38 37
Stomach Neonate: 6-8, 1.5-3 within a 1-2.5 1.3 (1.1-1.6) 2 (1.55-4.4) 1.7 (1.1 ± 3.4)30,a 2
few hours, back to 6-7 from (1.5-4.4)37
20-30 days with a gradual
reduction over 20-30
months to pH 1-27; Infant
and Toddler: 1.47; Child:
1.57; Adolescent: 1.57
1.4 (1.0-3.7)30
1.55 (0.95-2.6)37
1.4-1.7534
1.7 (1.4-2.0)38
Duodenum 8-12 years: 6.312 5-6.57 6.5 (6.2-6.7)38 5.67 ± 0.3020
Adolescent: 6.3-6.47 5.61 ± 0.4920
5.2-7.413
5.8-6.434
6.1 (5.9-6.4)38
Jejunum 8-12 years: 6.6-712 5.8-7.713 6.74 ± 0.3220 5.9-6.6 (inactive) and 6.1- 6.9 (6.5 ± 7.5)30,a6.8
7.3 (active) (proximal SI)36 (inactive) and 6.5-7.2
(active) (proximal SI)36
Adolescent (small 6.68 ± 0.3220 6.75 (6-8.53) (proximal 6.75 (6-8.53) (proximal
intestine): 6.4-7.47 SI)37 SI)37
7.1 (6.6 ± 7.9)30

5.5-7.434
5.9-6.8 (proximal SI)36
6.72 (6.15-7.35) (proximal
SI)37
Ileum 8-12 years: 7.312 6.6-7.713 6.9 ± 0.320 6.9-7.9 (inactive) and 6.8- 7.3 (6.9 ± 7.3)30,a
8.3 (active) (distal SI)36
6.9 ± 0.220 7.95 (7.75-9.2) (distal SI)37 8.2 (inactive) and 7.5-7.9
(active) (distal SI)36
30
7.4 (6.6 ± 8.1) (distal SI) 7.95 (7.75-9.2)
(distal SI)37
7.3-7.5234
7.3-7.7 (distal SI)36
7.5 (6.8-7.88)37
Caecum 8-12 years: 5.812 6-6.57 6.95 (6.3-7.4)37 6.95 (6.3-7.4)37
Adolescent: 5.97 4.7-6.813
5.7-6.3734
6.05 (5.3-6.55)37
Ascending colon Children (colon): 5.9-6.57 4.6-6.813 4.9-6.5 (inactive) and 4.7- 6.7 (6.3 ± 7.0) (right
7.2 (active) and 2.3-3.4 colon)30
(very active) (caecum/right
colon)36
Adolescent (colon): 5.9-6.57 5.8 (5.3 ± 6.3) (right colon)30 7 (6.3-7.8) (right colon)37 5.3 ± 0.3 (right colon35
8-12 years: 5.712 5.634 6.5 (inactive) and 5.3-6.8
6.8 ± 0.2 (right colon)35 (active) (caecum/right
5.7-6.8 (caecum/right colon)36 colon)36
5.88 (5.26-6.72) 7 (6.3-7.8) (right colon)37
(right colon)37
Transverse colon 8-12 years: 5.312 4.6-7.113
5.734
Descending colon 8-12 years: 6.012 5.5-7.413 6.5 (inactive) and 6.6-7.5 5.3 ± 0.7 (left colon)35
6.634 (active, left colon/rectum)36 6.5 (inactive) and 5.5-6.5
7.2 ± 0.3 (left colon)35 6.65 (5.9-7.7) (left colon)37 (active, left colon/
6.1-7.1 (left colon/rectum)36 rectum)36
6.12 (5.2-7.07) (left colon)37 6.65 (5.9-7.7)
(left colon)37
Rectum Neonate: 4.4-7.27 5.3-7.413
Infant and toddler: 5.9- 6.53-6.634
10.97
Children: 6.512
Adolescent: 6.57

Note: The number in () reflects a range. Right colon: the cecum, ascending colon, hepatic flexure and the right half of the transverse colon; Left colon: The left half of the
transverse colon, splenic flexure, descending colon, and sigmoid (http://training.seer.cancer.gov/colorectal/anatomy/).
a
Ileocecal resected.

pentaacetic acid (DTPA) by approximately threefold compared with (PEG-400), lactulose, L-rhamnose, and mannitol in Crohn's disease
healthy controls, whereas ulcerative colitis increased oral or ulcerative colitis patients49 Whether differences in Crohn's dis-
bioavailability of DTPA by fourfold.47,48 However, no changes in ease severity cause the inconsistent results reported in the litera-
oral bioavailability were observed for polyethyleneglycol-400 ture are worthy of further investigation. The markers used in
 J.P.F. Bai et al. / Journal of Pharmaceutical Sciences 105 (2016) 476e483
assessing permeability changes due to GI diseases are hydrophilic
in nature, and their absorption is mainly via paracellular tight
junctions. The increases in the paracellular permeability of some of
these markers due to GI diseases imply that GI diseases could affect
intestinal absorption of small, hydrophilic molecular drugs or ex-
cipients or food components. Systematic studies are needed to
determine the impact of GI disease severity on oral absorption of
small hydrophilic drugs or excipients or food components.
Jejunal mucosal morphology in geriatric subjects remains
similar to that in younger controls, including surface area/volume
ratio, enterocyte height, villus height, and crypt-to-villus ratio.50
Aging seems to have little influence on mannitol absorption,51
indicating similar paracellular permeation. Whether ontogenic
differences in intestinal permeability exist among children younger
than 17 years is unclear.
Secretion and Reabsorption of Bile Salts
In the proximal small intestine, bile salts facilitate dissolution of
lipophilic drugs and bicarbonate secretion from the pancreatic duct
neutralizes gastric acid and increase the luminal pH to be above pH
7 in the distal small intestine. Bile salts have also been shown to
behave as absorption enhancers for hydrophilic drugs.52
Many transporters are involved in the enterohepatic circulation
of bile salts, such as the hepatocellular bile salt export pump,
multidrug resistance protein MRP3, organic anion-transporting
polypeptides, and apical sodium-dependent bile salt trans-
porters.53 Diseases or genetic mutations that impair the function of
any one of these transporters could reduce intestinal concentra-
tions of bile salts, thereby affecting in vivo performance of a lipo-
philic drug in an oral dosage form.54 The bile acid pool increases
with development from neonates to adults.55 Aging reduces ab-
sorption of conjugated bile acids.56 Idiopathic bile acid malab-
sorption does not affect gastric emptying, but slows down small
intestinal and colonic transit, resulting in significantly longer
colonic transit times.57
Intestinal Transporters and Drug-Metabolizing Enzymes
Protein levels of small intestinal CYP 450 enzymes are CYP3A
(84%); CYP2C9 (14%); CYP2C19 (2%); CYP2D4 (0.7%); and CYP2J2
(1.4%).58 CYP2D6 protein is present at an approximately 1.8-fold
lower amount than CYP2J2. No detectable CYPP1A2, 2A6, 2B6,
2C8, and 2E1 proteins are observed in the human small intestine. As
CYP3A enzymes are most abundant, their developmental changes
have been studied extensively, whereas others have not received
much attention.
Impact of Age
Duodenal CYP3A4 mRNA level in infants was approximately
twice that in children aged 1-6 years and older.59 Duodenal CYP3A5
mRNA was slightly higher in infants than in older children and
adults, whereas CYP3A7 mRNA does not show developmental
changes. For several CYP3A enzymes, their mRNA expression does
not necessarily reflect actual activity because of the dissociation
between mRNA expression and protein level changes with age.60
CYP3A4 protein and activity showed the following rank order:
neonates < 3 months-2 years > 2-5 years < 5-11 years < 12 years
and older, with the level in neonates approximately twofold lower
than that of children aged 12 years and older.61 Consistently, the
bioavailability of midazolam, a CYP3A substrate, in preterm neo-
nates was 20% higher than in adults.60 Another important factor for
understanding oral absorption in children, infants, and neonates is
the correlation between individual transporter activities and age.
481
Intestinal and hepatic expression levels of key transporters
increased from neonates to adults,62 indicating that oral absorption
and drug disposition could be affected by age. ABCC2 encodes the
ATP-binding cassette, sub-family C, member 2 protein known as
MRP2, and ABCB1 encodes the ATP-binding cassette, sub-family B
(MDR/TAP), member 1 protein known as MDR1. Intestinal ABCB1
mRNA expression in neonates was 1.8-fold lower than in infants
and adults, whereas intestinal ABCC2 mRNA expression in neonates
and adults was similar, but approximately 30-fold lower than in
infants.62 For intestinal SLCO2B1, which encodes the solute carrier
organic anion transporter family, member 2B1 (also known as
OATP2B1) neonates had approximately twofold higher mRNA than
infants and adults. Of note, the level of mRNA expression does not
necessarily reflect the level of protein expression or activity.
Further studies are needed with respect to developmental changes
in the protein level of each key transporter involved and their
impact on drug absorption.
The effects of aging on intestinal expression levels as well as
activities of transporters and of CYP450 enzymes are unknown,
although aging reportedly affected activity and expression of
P-glycoprotein in lymphocytes.63
Impact of GI Diseases
In Crohn's disease patients, intestinal mRNA levels of CYP3A4,
CYP3A5, and MDR1 (encoding P-glycoprotein) were significantly
higher than in controls.64 Chronic IBD, including ulcerative colitis
and Crohn's disease, did not affect the expression of CYP2E1, CYP3A,
and CYP2D6 compared with controls who had clinical irritable co-
lon but no clinical or histological signs of inflammation.65 However,
chronic IBD has a higher expression than controls of CYP1A1
protein in the colon. More studies are needed to understand how
inflammatory intestinal disease could affect the GI first pass
metabolism and, consequently, oral bioavailability.
Other Factors that Could Contribute to Bioavailability of Oral
Drug Products
Hepatic Transporters and Enzymes
Aging affects liver size and weight, blood flow to the liver,
protein level, plasma albumin, and renal clearance.66 An in vitro
biopsy study of >200 samples revealed that expression of hepatic
CYP450 proteins increased between 30 and 39 years old; decreased
at 40 years old, with the decline leveling off by age 69; and
decreased further after age 70, with a 32% reduction.67 Interest-
ingly, a recent study of in vitro comparisons suggested that aging
did not impact CYP450 enzyme activities including 1A2, 2A6, 2B6,
2C8, 2C9, 2C19, 2D6, 2E1, 3A4, and 4A11.68 Further studies are
warranted to understand how aging impacts CYP450 enzyme ac-
tivities. With the understanding that in vitro and in vivo conditions
are different, only in vivo pharmacokinetic studies are relevant for
understanding the effects of aging on drug elimination and first
pass extraction, and oral bioavailability.65 Importantly, aging
reduced in vivo clearance of drugs that are substrates of CYP1A2,
2C9, 2C19, 2E1, and 3A4/5, but not 2D6.66
Hepatic transporters play a significant role in drug clearance,
such as OATP1B1 (organic anion transporting the polypeptide
encoded by SLCO1B1, solute carrier organic anion transporter
family, member 1B1) for statins; however, studies on how aging
affects hepatic transporter activities are lacking. In the elderly,
plasma levels of HMG-CoA reductase inhibitory activity of statins
increased by roughly 45% compared with younger adults,69 indi-
cating that aging reduced their clearance.
482 J.P.F. Bai et al. / Journal of Pharmaceutical Sciences 105 (2016) 476e483
Discussion
Oral bioavailability or local availability of a drug product is the
outcome of interaction between the patient's physiological char-
acteristics and the characteristics of a drug product. Healthy adults
and patients of different demographic characteristics share simi-
larities in some GI physiological parameters that are relevant to
drug bioavailability but differ in others; it is important to determine
what GI physiological parameters are crucial to the oral bioavail-
ability or local availability of a drug product to fully assess the
clinical variability and benefits of a drug product across all patient
groups. The presence of a GI disease such as IBS, UC, or CD could
further increase the complexity to the drug product/GI physiology
interaction and consequently influence oral bioavailability or local
availability of a drug product. Understanding how GI physiological
characteristics that are relevant to the oral bioavailability of a drug
product differ among patients because of aging, ontogeny, and
diseases is crucial, especially for the non-immediate formulations.
The majority of studies investigating GI physiology were per-
formed following an overnight fasting. However, some drug prod-
ucts are to be administered before a meal, and some are taken
without regard to meal, whereas others are taken with a meal or
after a meal. The fed state impacts the GI transit and pH profile, as
well as oral absorption of drugs. For example, meals could stimulate
small intestinal transit.70 Most oral dosage forms completely
disintegrate and release the enclosed dosage for absorption when
entering the small intestine, except those designed to release in the
colon. When assessing in vivo performance of modified release
dosage forms designed to deliver a drug in the colon, the effect of
meals should be considered so that a suitable formulation could be
designed.
The markers used to assess the impact of GI diseases on intes-
tinal permeability are hydrophilic and mainly absorbed via the
paracellular route, thereby providing relevant references for pro-
jecting possible changes of intestinal absorption of locally acting
small molecular, hydrophilic drugs, nutrients such as glucose, and
excipients used in food or drug products. The decrease in oral
bioavailability of vitamin D in patients with Crohn's disease
compared with healthy controls is not well understood.71 A study of
5-amino salicylic acid (5-ASA) formulated in a colon delivery sys-
tem showed that patients with Crohn's disease or ulcerative colitis
and healthy controls had similar AUC or Cmax values or exposures of
its metabolite, acetyl-5-ASA.72 Therefore, more studies are needed
to under-stand how GI disease severity affects oral absorption of
drugs or excipients.
The composition of intestinal bile salts that are secreted in
response to food intake could affect in vivo performance of oral
products of lipophilic drugs. Aging is associated with reduced bile
acid synthesis.73 Ontogenic changes in bile acids secreted in chil-
dren are, however, not known, even though there are published
studies in rats.74 Enterohepatic recycling could affect oral
bioavailability of drug but little is known regarding how aging, GI
diseases, and ontogenic development affect enterohepatic recy-
cling. Furthermore, an emerging health research area is how gut
microorganisms intimately control our immune system and ulti-
mately impact our health.75 The impact of gut microbiomes on the
pH, permeability and colonic transit could presumably contribute
to the in vivo performance of locally released formulations in pa-
tients with diverse demographic characteristics. Further research is
needed to fill in this gap.
In summary, our knowledge of GI physiology in relation to the oral
bioavailability or local availability of a drug product has enabled
development of a fit-for-purpose oral formulation for a drug and
assessment of its in vivo performance with a certain level of confi-
dence in various subpopulations of the target disease population.
There are, however, knowledge gaps to be addressed in order to have
an accurate assessment of the in vivo performance of an oral product
in its target disease population of diverse patient characteristics. As
more data and knowledge become available, modeling tools such as
physiologically-based systems modeling approaches could be more
realistic and physiologically meaningfully.
Acknowledgments
The authors would like to acknowledge the kind comments
from Drs. Xinyuan Zhang, Andrew Babiskin, Robert Lionberger
(Director, Office of Research and Standards) of Office of Generic
Drugs, Vikram Sinha (Director, Division of Pharmacometrics) and
Darrell Abernethy (Associate director for Drug Safety) of Office of
Clinical Pharmacology, as well as Dr. Donna Griebel (Director, Di-
vision of Gastroenterology and Inborn Errors Products) of Office of
New Drugs.
Author contributions: J. P. F. B. conceived the project, designed
the project, and wrote the manuscript. G. B. and A. M. provided
advice/comments/review of the manuscript to help complete the
project.
Conflict of interest/disclose: The authors declare no conflicts of
interest.
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