BIOPHARMACEUTICS & DRUG DISPOSITION, VOL.

16, 351-380 (1995)

REVIEW ARTICLE
COMPARISON OF THE GASTROINTESTINAL
ANATOMY, PHYSIOLOGY, AND
BIOCHEMISTRY OF HUMANS AND
COMMONLY USED LABORATORY ANIMALS
TUGRUL T. KARARLI
G. D . Searle & Co.. 4901 Searle Parkway, Skokie. IL 60077, U.S.A.

ABSTRACT
In addition to metabolic differences, the anatomical, physiological, and biochemical
differences in the gastrointestinal (G.I.) tract of the human and common laboratory
animals can cause significant variation in drug absorption from the oral route. Among
the physiological factors, pH, bile, pancreatic juice, and mucus and fluid volume and
content can modify dissolution rates, solubility, transit times, and membrane transport
of drug molecules. The microbial content of the G.I. tract can significantly affect the
reductive metabolism and enterohepatic circulation of drugs and colonic delivery of
formulations. The transit time of dosage forms can be significantly different between
species due to different dimensions and propulsive activities of the G.I. tract. The lipid/
protein composition of the enterocyte membrane along the G.I. tract can alter binding
and passive, active, and carrier-mediated transport of drugs. The location and number
of Peyers patches can also be important in the absorption of large molecules and
particulate matter.
While small animals, rats, mice, guinea pigs, and rabbits, are most suitable for
determining the mechanism of drug absorption and bioavailability values from powder
or solution formulations, larger animals, dogs, pigs, and monkeys, are used to assess
absorption from formulations. The understanding of physiological, anatomical, and
biochemical differences between the G.I. tracts of different animal species can lead to the
selection of the correct animal model to mimic the bioavailability of compounds in the
human.
This article reviews the anatomical, physiological, and biochemical differences
between the G.I. tracts of humans and commonly used laboratory animals.
KEY WORDS

gastrointestinal tract; anatomy; physiology; biochemistry; humans; animals

COMPARATIVE ANATOMY OF THE G.I. TRACT

The stomach and small intestine

The gross morphology of the mammalian G.I. tract differs considerably

among species although it exhibits some basic structural similarities. The
CCC 0 142-2782/95/05035 1-30
01995 by John Wiley & Sons, Ltd.

Received 8 January I994

352

T. T. KARARLI

rat

ox

llama
Stratified sq. nonglandular

Q
>:,.:

Cardiac

Proper gastric

H pyioric
Figure 1. Variations in the type and distribution of gastric mucosa. Stomachs are not drawn to
scale. From reference 1, with permission

overall G.I. morphology is greatly influenced by adaptation, nature of food,

frequency of food intake, need for food storage, and body size and shape.
Diagrams of the human, rat, dog, horse, cow, llama, and pig stomachs are
shown in Figure 1. The stomachs of rodents are divided into a glandular and a
non-glandular portion. The non-glandular stomach is generally thin walled and
transparent. The glandular stomach is thick walled. The non-glandular part of
the stomach is lined by keratinized stratified squamous epithelium and is used
in the storage and digestion of food. The glandular part is covered by columnar
epithelia. The lamina propria in the glandular part is occupied by simple
tubular gastric glands containing mucus-secreting neck cells, pepsinogensecreting chief cells, and HC1-secreting parietal cells.' The stomach of the
rabbit is simple and lacks specialized regions. It is thin walled and relatively
large?

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(3.1. ANATOMY, PHYSIOLOGY, AND BIOCHEMISTRY

Table 1. Lengths of parts of the intestine at autopsy. (From reference 1, with permission)

Relative
length
Animal

Part of intestine

(%I

Average
absolute
length
(m)

Ratio of body
length to
intestine
length

Horse

Small intestine
Cecum
Large colon
Small colon
Total

75
4
11
10
100

2244
1 .oo
3.39
3.08
29.91

1:12

ox

Small intestine
Cecum
Colon
Total

81
2
17
100

46.00
0.88
10.18
57.06

1:20

Sheep and
goat

Small intestine
Cecum
Colon
Total

80
1
19
100

26.20
0.36
6.17
32.73

1:27

Pig

Small intestine
Cecum
Colon
Total

78
1
21
100

18.29
0.23
4.99
23.51

1:14

Dog

Small intestine
Cecum
Colon
Total

85
2
13
100

4.14
0.08
0.60
4.82

1:6

Cat

Small intestine
Large intestine
Total

83
17
100

1.72
0.35
2.07

1:4

Rabit

Small intestine
Cecum
Colon
Total

61
11
28
100

3.56
0.61
1.65
5.82

1:lO

In the human, pig, dog, and monkey, the stomach is of glandular type and is
lined with cardiac, gastric, and pyloric mucosa (Figure 1). The pig stomach is
two to three times larger and the cardiac mucosa occupies a greater portion of
the stomach compared to the human stomach. Both gastric and pyloric mucosa
contain parietal and chief cells. The cardiac cells secrete mainly mucus.
The occurrence and distribution of the cells in the gastric glands differs
considerably among the mouse, rat, hamster, guinea pig, gerbil, and rabbit.3 In
mice, rats, hamsters, and gerbils, the lower one-third of the glandular lamina
propria is occupied by a varying proportion of parietal and chief cells. In

354

T. T. KARARLI

rabbits, the predominant chief cells are distributed in the lower three-quarters
of the glands intermingling with parietal cells, but in guinea pigs the chief cells
are not discernable. In hamsters there is, however, a gradual increase of chief
cells from the junction between non-glandular and glandular stomach toward
the pyloric region. In all these species, the parietal cells are the dominant cell
type in the upper one-third of the gastric glands, often extending up to the neck
of the gland interspersing between mucus neck cells and occasionally chief cells.
The relative and absolute lengths of the parts of the small intestine for
various mammals are given in Tables 1-3. These data were obtained from the
post mortem examination of the tissues. The dimensions of the tissues in vivo
appear to be smaller. For example, the post mortem length of the small
intestine in humans is around 7 m, while the estimated length in vivo is close to
3 m.6
The Beagle dog small intestine is 225-290 cm long, of which the first 25 cm is
~ , ~structure of the digestive tract
the duodenum and the last 15 cm is i l e ~ m .The
of the monkey, pig, dog, pony, rabbit, sheep, guinea pig, and rat is illustrated
in Figure 2. The digestive tract of the dog is relatively short and simple. The pig
also has a simple G.I. tract; however, the relative length of the pig G.I. tract is
longer than that of the dog (Table 1). The sheep small intestine is the longest
among common laboratory animals. The mouse small intestinal length is about
35-45 ~ r n The
. ~ diameter of the small intestine in the human is 5 cm (Table 2),
in the pig, 2.5-3.5cm, in the beagle dog, I . O C ~in, ~the Rhesus monkey,
1.2-2 cm, and in the rat, 0.3-0-5 cm (Table 3).1 The rabbit small intestine
consists of a long duodenum and mesenterical jejunum and ileum with the
terminal portion of the latter expanded as the rounded sacculus rotundus. The
ileum possesses a thinner wall than the more vascular and thick-walled jejunum
and duodenum.2
The small intestine is the major site for the absorption of nutrients and
drugs. This is accomplished through the enormous surface area available in this
organ. The luminal surface of the small intestine is covered by villi. Columnar
absorptive cells or enterocytes cover over 90% of the cell population on the
villi surface." The luminal surface of the enterocytes contains fine extentions
called microvilli. The surface area of a mucosal cylinder the size of the small
intestine would be about 0.33 m2. This value increases to 120 m2 with the villi
and microvilli extensions (Table 2). The number of villi per square millimeter in
the freeze-dried jejunum and ileum of the rat, hamster, and dog are relatively
constant and were found to be 23 and 38, 25 and 25, and 23 and 23,
respectively.12 The villi have characteristic shapes and patterns in different
species. For example, villi are finger shaped in the mouse, pig, and human and
tongue shaped in the rat.1 In stump-tailed monkeys (Macaca speciosa) the villi
are tongue shaped in the duodenum and finger shaped in the jejunum and
i1e~rn.l~
The number of microvilli per unit area of villi surface shows some
variation among different animals. In the rat, there are 65 microvilli per square
micrometer of villi surface: in the dog the number is 34." However, after taking

G.I. ANATOMY, PHYSIOLOGY, A N D BIOCHEMISTRY

355

356

T. T.KARARLI

Table 2. Organ size, surface area, and presence of surface processes (villi) in the
alimentary canal of humans. (From reference 4, with permission)
Average
diameter

(m

Absorbing
surface area
(mZ)

Presence of
Process F,
MAV, MIVa

0.07
0.02
-0.11

none
none

Anatomic unit

Average length
(a)

Mouth cavity
Esophagus
Stomach

15-20
25
20

10
2.5
15

25

Jejunum

300

Ileum
CeCm

300
10-30

5
7

Colon

150

Rectum

15-19

2.5

Duodenum

--

0.09

60

60

-0-05

-0.25
0.015

F: + + +
MAV none
MIV: none
F: +
MAV: + + +
MIV: + + +
F: +
MAV: + + +
MIV: + + +

F: +
MAV: +
MIV: +
F: + MAV: noneMIV none
F: + MAV: none MIV: none

aF, folds; MAV, macrovilli; MIV, microvilli.

Table 3. Length and diameters of parts of rat intestinal tract (lengths post mortem
without fixation; diameters are to be taken as approximations). (From reference 5, with
permission)

Duodenum
Jejunum
Ileum
CeCUm
Colon
Rectum
TOTAL

Length (mm)

Diameter (mm)

95-100
900-1350
25-35
50-70
90-110
80

2.5-3
4-5
3-5
10
10-3
3-1 0

1200-1700

into account the sizes of the villi, the effective surface area per unit villus
surface becomes a constant value of around 25 pmZ pm-2. In the dog jejunum,
compared with the ileum, the villi and microvilli are longer and wider and the
enterocytes are more numerous per unit weight of tissue.14

G.I.ANATOMY, PHYSIOLOGY, AND BIOCHEMISTRY

357

The colon

The colon plays a major role in the absorption of water, Na+ and other
minerals. The colon contains the largest population of microorganisms in the
G.I. tract and is the major site of production and absorption of volatile fatty
acids in the sheep, pig, rabbit, rat, dog, and human.15 The luminal surface of
the colon does not have villi but is divided into geographical areas by
transverse furrows. The colonic enterocyte differs slightly from that of the
small intestinal variety. Colonic microvilli are less closely packed.12J6
There are some significant species differences in the anatomy of the colon
(Table 1 and Figure 2). In humans, the colon length vanes from 90 to 150cm
and consists of the ascending, transverse, descending, and sigmoid sections. All
sections of the colon in humans, monkeys, and pigs are sacculated. The dog
colon does not have sacculations and the overall length is about 25 cm and the
diameter is 2 ~ m The
. ~ dog colon is also divided into ascending (5cm),
transverse (7 cm), and descending (12 cm) portions.* The ascending colon is
20cm in humans. The pig ascending colon is longer than the dog and the
monkey ascending colon. Humans have a poorly defined cecal region, which is
continuous with the colon. The pig cecum is several orders of magnitude larger
than that of the human. In dogs, the cecum is a lateral appendage directly out
of the line of intestinal movement. Guinea pigs have a complex colon. Their
cecum is three times as large as their stomach and it is sacculated. The proximal
colon is enlarged and differentiated. It is capacious and never empty. The large
and sacculated rabbit cecum is characterized by a spirally arranged constriction
related to the internal folding of the mucosa. The first part of the rabbit colon
is structured like a cecum and constitutes the ampulla caecalis coli. The colon is
characterized by sacculations, or haustra.2 The rat cecum is also large, but its
colon is neither sacculated nor long.

THE PHYSIOLOGICAL FACTORS

G.I. p H values

The solubility and dissolution rate of drugs are higher when they are in the
ionized form. Passive membrane absorption for lipophilic drugs is favored in
the unionized state. Therefore, the pH of the fluids throughout the G.I. tract is
critical in the dissolution, solubilization, and absorption processes of ionizable
drugs.
The source of hydrogen ions in the G.I. tract is secretion by the parietal cells
of the stomach. Secretion is controlled by both neural (n. vagus) and hormonal
(gastric) feedback mechanisms. When the acidic content of the stomach reaches
the duodenum it stimulates the secretion of an alkaline fluid from the pancreas
rich in bicarbonate anions (pH 8). This fluid, along with the bile and alkaline

358

T. T. KARARLI

Table 4. Comparison of gastric acid secretion data of humans, dogs, swine, and rhesus
monkeys. (From reference 10, with permission)
Parameter

Human

Dog

Swine

Monkey

Stomach capacity (L)

Basal volume (L)
BAO
Volume (mL min-')

1-1.6

6-8

0.024a

0.1
0.008b

0'3-1.5

1.05

2-5

0.1

Similar to
humans unless
stressed
Similar to humans
unless stressed

18-23

39

Fasted

1.7 (1.4-2.1)c

1.5

Fed (during meal)

5.0 (4.3-5.4)d 2.1 *0.1

Rate (mEq h-')

PA0
Rate (mEq h-')
PH

5.6 pg h-'

1.25 pg h-'
2.7
3.7- (n=20)
1.61.8
(0-8-3 .O)d
< 2 (n= I)

(SD)
"from 17.
bFrom 18.
BAO, basal acid output.
PAO, peak acid output.
CInterquartilerange.
dRange.

fluids, secreted by the mucosal lining of the small intestine, neutralizes the
acidic contents reaching the duodenum.
The gastric acid and fluid secretion rates, gastric volume, and pH values for
humans, beagle dogs, pigs, and Rhesus monkeys are given in Table 4. In dogs,
the gastric acid secretion rate at the basal state is low. Therefore, the stomach
pH of the dog can be as high as its duodenal contents in the unstimulated
state.I9 Following stimulation (i.e., food, histamine), gastric acid secretion rates
in dogs exceed those of the human and pig (Table 4). In humans, the stomach
pH after food is initially higher due to the strong buffering action of food.
However, the pH returns to a low value after about one hour (Table 4).
Table 5 lists the pH values of the different sections of the G.I. tract of 15
animal species. The pH values of the fluids throughout the G.I. tract of humans
and of two rat species are also given in Tables 6 and 7, respectively. In the
stomachs of all the animals examined, except the rabbit, the anterior (cardiac)
region was found to have a higher pH value than the pyloric region since the
parietal cells tend to be localized in the lower part of the stomach. In the rabbit,
both portions had low pH values. The high acid value throughout the rabbit
stomach is probably due to this organ not being separated into compartments,
thereby permitting its contents to mix. Generally, in the small intestine,

3
3
6
3
3
3
20
11
6
7
3
3
3
6
3

4.8
5.5
5.0
6.0
6.4
5.4
4.3
1.9
4.5
5.0
4.5
6.9
5.5
4.9
5.0

A
P
2.8
3.4
4.2
2.4
3.0
3.3
2.2
1.9
4.1
3.3
3.1
2.9
3.8
4.2
4.5

Stomach

6.8
7.8
7.0
7.4

6.6
7.0
6.2
6.5

6.1
6.7
5.8
6.1

5
6.0
6.6
7.0
7.3
7.7
7.3
6.9
7.5
8.1
6.8

3
5.8
6.2
6.7
7.0
6.6
7.0
6.2
6.8
7.7
6.7

5.6
6.2
6.2
6.7
5.7
6.7
6.0
6.0
7.6
6.5

Small intestine portion

A, anterior portion of stomach; P, posterior portion; Feces, contents of posterior rectum.

Sheep
Horse
Pig
Rabbit
Guinea pig
Rat
Mouse
Hamster
Gerbil
Fowl
Duck

ox

Monkey
Dog
Cat

Animals

No.
examined

7.1
8.2
7.8
8.0

6.0
7.5
7.6
7.9
8.0
7.9
7.5
8.0
8.1
7.1

7.1
7.0
7.0

5.0
6.4
6.0
7.0
7.3
7.0
6.3
6.6
7.0
6.8

Cecum

pH value (median for different animals) of contents of

7.4

5.1
6.5
6.2
7.4
7.8
7.4
6.8
7.2
6.7
6.6

Colon

7.5
7.6
7.3

5.5
6.2
7.0
7.5
8.0
7.5
7.1
7.2
6.7
6.9

Feces

Table 5. pH values of the contents of different parts of the alimentary tract in animals of 15 different species. (From reference 20, with
permission)

0
cl

5U

"4

"5
z

9
7

360

T. T. KARARLI

Table 6. The pH values of the human G.I. fluids. (From reference 21,
with permission)

Anatomical site

Range

Stomacha

1.5-3.5

Duodenumb

5-7
6-7
7.0
5-5-7.0
7

Jejunum
Ileum
Colon'
Rectum

"Can be as high as 7.
bpH of chyme entering duodenum can be as high as 6.
'Depends on type of food ingested.

Table 7. The pH values of the rat G.I. fluids. (From reference 22, with permission)

Lister hooded rats

Anatomical region

Fasted

Fed

Forestomach
Glandular stomach

4.3 (0.5)
4.0 (0.4)

5.1 (0.2)

Duodenum

7.1 (0.1)
8.0 (0.1)

6.9 (0.1)
7.4 (0.1)
6.4 (0.1)
6.8 (0-2)

Jejunum-ileum
CeCUm
Colon

7.2 (0.1)
7.6 (0.1)

3.1 (0.3)

Wistar rats
Fed
4.5 (0.2)
2.3 (0.2)
6.9 (0.2)
7.8 (0.1)
6.7 (0.1)
7.1 (0-6)

although the pH values were variable from animal to animal, the measured pH
became progressively more alkaline in the distal portions within the same
animal. In the monkey, the pH value of the distal ileum was found to be the
lowest among the animals studied. The pH values in the large intestine were
more acidic than the pH values recorded from the small intestine, due to
fermentation.
Bile fluid

The importance of bile fluid in the absorption of lipid-soluble vitamins,

steroids, and dietary lipids has long been recognized (see 23 for a review). Bile
salts aid in the intestinal absorption of lipophilic compounds by enhancing the
dissolution rate and solubility. They are also critical for the lymphatic uptake
of lipids and lipid-soluble drugs (see 24 for a review). The improved dissolution
rate in the intestine may be due to the improvement of the wetting properties of
the solid drug or the increased solubility of drug in micellar sol~tions.~5
In the
in vivein vitro correlations of highly lipophilic drugs, one must know whether
the compound in question is micellarly solubilized.26Bile fluid can be the major
route of excretion for drugs with molecular weights greater than 400.27

361

G.I. ANATOMY, PHYSIOLOGY, AND BIOCHEMISTRY

Table 8. The rates of bile flow and composition. (From reference 23, with permission)
Humana

Rabbit"

Monkey

Dog

Rat

Bile flow (mL d-' kg-I)

TBS rate
(mmol d-' kg-I)
PL rate (mmol d-' kg-I)
CH rate
(mmol d-I kg-I)
TBS (mmol L-l)
PL (mmol L-l)
CH (mmol L-I)

2.2-22.2

3-45

130

19-32

19-36

0.36
0.08

16-2.9

0.014
22
4.3
0.75

6-24

0.85-1
0.15-0.3

40-90

0-03-0.035
17-1 8
26-3.5
04-06

"From 10.
TBS, total bile salt; CH, cholesterol; PL, phospholipid.

Bile is produced in the liver and secreted through the hepatic duct into the
gallbladder. During food intake, following stimulation by secretin and
cholecystokinin, bile fluid is secreted into the duodenum. The circulation of
bile salts is confined to the enterohepatic circulation. This includes the liver,
gallbladder, biliary tract, and portal venous system. In humans, dogs, and cats
the common bile duct enters the duodenum at the duodenal papilla. Its orifice
is surrounded by the sphincter of Oddi and usually unites with the pancreatic
duct just before entering the duodenum. In rabbits and guinea pigs the
pancreatic duodenal papilla is dislocated distally with respect to that of the
biliary system.28In the rat, there is a strict interdependence among biliary and
pancreatic ductal systems, demonstrated by the fact that pancreatic ducts flow
directly into the common bile
In the rat, the bile duct is 12-45mm in
length and 1mm in diameter and the duodenal papilla is 7-35 mm distal to the
pyloric ~alve.5.~9
Bile contains bile salts, cholesterol, and phospholipids. Bile salts are the Na+
and K + salts of the bile acids conjugated to the glycine and taurine. While in
humans cholic acid is the major bile acid, hyocholic acid is the major bile acid
in pigs.'O In dogs, three or even four hydroxyl-group-containing bile acids are
encountered.lo
The rate of bile fluid secretion within a given animal is dependent on the
circadian rhythm of the animal.30In animals not possessing a gallbladder, e.g.,
rat, horse, and pigeon, bile fluid is secreted continuously in dilute form and
large volumes. Bile fluid composition and secretion rates in the Rhesus
monkey, dog, rat, and pig are given in Table 8. The total bile salt
concentrations and secretion rates are the highest in the dog and the lowest
in the monkey.

362

T. T. KARARLI

Table 9. Location of the gut flora in various species: bacterial counts in various parts of
the gastrointestinal tract; log,, number of viable organisms per gram wet weight. (From
reference 34, with permission)
Location
Stomach
Proximal small intestine
Distal small intestine
Large intestine
Rectum and feces

Human

Rabbit

Guinea pig

Rat

Mouse

0-5
0-5
6-7
7-10
1G11

Cb6
Cb5
G7
8-9
9-10

5 4
5-6

7-9
6-8
7-8
8-9
9-10

7-9
7-9
7-8
8-9
9-10

6 7
8-9
9-10

G.I. tract microflora

The G.I. tract microflora can metabolize a variety of chemicals, which can
lead to reduced absorption in the intestine. The toxicological consequences of
the metabolism can be significant depending on the chemical metabolized.3'
The hydrolysis of glucosides, glucuronides, sulfate esters, amides, esters,
dehydroxylation, deamidation, decarboxylations, dealkylations, deamination,
reduction of double bonds, nitro, and diazo groups, acetylation, and
esterification are some metabolic reactions that take place in the presence of
gut mi~roflora.~'
j3-glucuronidase and glucosidase activities of the colonic
bacteria have been exploited as a way to deliver compounds and formulations
into the
There are almost 400 different microorganisms in the G.I. tract.33 Drasar
and coworkers reported that there are considerable interspecies differences with
regard to location and quantity of the microflora along the gut (Table 9).34
While in the human and rabbit the upper G.I. tract contains few organisms,
bacteria are found in large numbers in the stomach and upper intestine of other
animals (Tables 9 and 10). While bacteroides and bifidobacteria are the most
prevalent species in the upper intestine in humans and rabbit, other varieties
are also encountered in other animals. All animals including humans display
comparable flora in the lower intestine (Table 10).
The best known example of bacterial metabolism of foreign compounds in
the intestine is the hydrolysis of glucuronide conjugates. This reaction plays a
major role in the enterohepatic circulation of compounds. The differences
between the j3-glucuronidase activities of the upper and distal small intestine of
the human, rabbit, guinea pig, rat, and mouse are given in Table 11. Table 1 1
shows that the mouse has the largest P-glucuronidase activity in both the upper
and lower intestine and humans have the least.

Mucin
The epithelial surface of the G.I. tract is covered by a water-insoluble, freeflowing and viscous gel; mucin. Mucin consists of a large protein core with

363

G.I. ANATOMY, PHYSIOLOGY, A N D BIOCHEMISTRY

Table 10. Numbers of different kinds of organism in the contents of different parts of
the alimentary tract in animals of 20 different species. (From reference 20, with permission)

Species of
animal
(number
examined)

Log,, viable count (median for animals of stated species)

per gram contents of

Organisms

Monkey (3) E. coli

C . perfringens
Streptococci
Lactobacilli
Yeasts
Bacteroides
E. coli
Dog (3)
C. perfringens
Streptococci
Lactobacilli
Yeasts
Bacteroides
Sheep (3)
E. coli
C. perfringens
Streptococci
Lactobacilli
Yeasts
Bacteroides
Horse (3)
E. coli
C. perfringens
Streptococci
Lactobacilli
Yeasts
Bacteroides
Pig (20)
E. coli
C. perfringens
Streptococci
Lactobacilli
Yeasts
Bacteroides
Rabbit (1 1) E. coli
C. perfringens
Streptococci
Lactobacilli
Yeasts
Bacteroides
Guinea pig (6)E. coli
C. perfringens
Streptococci
Lactobacilli
Yeasts
Bacteroides

Stomach

Small intestine portion

3.0
1.7
6.5
8.7
5.2
N
4.5
5.2
5.5
4.5
N
N
3.0
N
6.8
6.7
N
N
4.5
N
6.5
5.8
N
N
5.3
2.4
6.0
8.6
4.3
N
N
N
N
N
N
4.2
N
N

2.6
1.7

2.4
2.0

5.0

5.0

8.0
5.3
N
4.4
5.2

7.8
5.1
N
2-7
4.5
5.9
3.3
N
N
N
N
2.7
4.5
N
N
3.0
N

3.4
N
5.7
8.6
5.8
N
3.4
4.8
5.6
4.7
N
N
3.0
1.7
3.7
4.3
N
N
3.7
N
5.6

3.4
N
6.4
8.6
5.7
N
4.4
5.2
5.8
4.7
N
N
3.7
2.0
4.3

4.7
2.4
6.7
9.0
5.6
N
5-2
6.2
7.0

N
N
4.2
N
5.7

5.0

5.0

N
N
3.7
N
4.5
7.0
3.9
N
N
N
N
N
N
4.1
N
N
5.2
7.6
4.2
N

N
N
4.5
1.7
6.0
7.6
4.4
N
N
N
N
N
N

5.0

7.6
4.2
N

5.5

4.2
N
N
1.7
1.7
3.5
4.0
N
N
2.5
N
5.0
4.5
N
N
3.0
N
4.4
7.0
4.3
N
N
N
N
N
N
4.2
N
N
4.8
7.6
3.7
N

5.0

4.3
N
N
3.4
N
4.2
6.5
3.9
N
N
N
N
N
N
3.8
N
N
4.0

6.7
3.7
N

5.0

5.0

N
N
5.7
8.4
4.3
N

5.8

N
N
4.7
2.7
5.5

5.4
N
N
5.4
N
6.1
4.4
N
N
5.3
3.0
6.5
8.0
4.0
N
N
N
N
N
N
6.7
N
N
5.9
8.7
4.4
N

Cecum Feces
5.7
2.6
8.0
9.7
6.4
9.0
7.2
7.7
8.2
8.7
N
8.5
5.4
3.3
6.1
5.0

N
4.2
3.7
N
6.0
5.6
N
5.8

6.5
N
7.0
8.6
4.0
7.4
N
N
4.0
N
N
8.5
N
N
6.5
9.0
4.2
7.8

6.4
N
7.8
9.5
5.2
9.0
7-2
7.8
9.3
9.0
N
9.3
5.7
2.0
6.5
5.2
N
N
3.4
1.7
5.9
5.4
N
6.0
6.8
N
7.2
8.8
4.2
7.6
N
N
4.7
N
N
8.7
N
N
6.0
8.8
4.0
7.6

(continued)

364

T.T.KARARLI

Table 10. (continued)

Log,, viable count (median for animals of stated species)
per gram contents of

Species of
animal
(number

examined)

Organisms

White rat (7) E. coli

C. perfringens

Streptococci
Lactobacilli
Yeasts

Bacteroides
White mouse E. coli
(3)

C. perfringens
Streptococci

Lactobacilli
Yeasts
Bacteroides

Stomach

Small intestine portion

2.0
N

N
N
4.2
7.5
6.0
N
N
N
5.3
7.0
6.3
N

N
N
3-0
7.0
6.0
N
1.7
N
5.0
6.3
6.2
N

3.4
N
4.7
7.4
6.7
N
2.0
N

3.6
N
4-7

4.5
N

7.8

8.0
6.7
N
4.0
N
6.7
8-0
6.7
N

5.0

8.4
6.2
N
2.0
1.7
6.0
7.7
6.7
N

5.0

6.8
6.0
N

6.8
N
3.4
N
6.0
7-5
6.0
N

Cecum Feces

5-0

5.2
2.0
6.0
8.4
7.3
8.2
5.4

N
7.0
8.8
7.0
9.4

5.6
1-7
6.2
8.6
7.0
8.4
6.0
1.7
6.7
9-0
6.6
9.4

A = anterior; P =posterior.

Table 11. Estimated bacterial P-glucuronidase activity in the

proximal small intestine (PSI) and distal small intestine (DSI) of
humans and four laboratory animal species. (From reference 35, with

permission)
Estimated P-glucuronidase activitya
Animal species
Human
Rabbit

Guinea pig
Rat
Mouse

DSI

PSI

0.02
2-4
2.7
304
1200

0.9
45.4
139
1341
5015
~~

"Micromoles of phenolphthalein-P-D-glucoside
degraded per hour per gram
of intestinal contents.

oligosaccharide side chains (1-30 units) attached on every other fourth amino
acid in the backbone. N-acetylgalactosamine, N-acetylglucosamine, Dgalactose, L-fucose, and sialic acid constitute the sugar molecules in
oligosaccharides. The last two sugars occupy the free end of the
oligosaccharide moieties.36Because of these anionic sugar end groups, mucin
has an overall anionic character. Mucin is important in the mucosal adhesion
of dosage formulations, which may lead to prolonged G.I. transit.36 In the
stomach and duodenum, the neutralization of the acid by the mucosal
bicarbonate in this stagnant gel layer provides protection for mucosa from

G.I. ANATOMY, PHYSIOLOGY, AND BIOCHEMISTRY

365

Table 12. Some physical properties of G.I. mucin. (From reference 36, with permission)
Thickness of stomach
mucin (p)
Species

Fundas

Antrum

Rat

166 (10)
234 (9)
425 (7)

343 (43)
473 (48)
576 (81)

Guinea pig
Dog
Rat intestinal mucin
Pig gastric mucin

Effective
hydrodynamic
Native
volume
concentration

81.4 mL g-I
40 mL g-I

55 mg mL-'

luminal acid and pepsin.37The stomach mucin thickness vanes among animal
species (Table 12).
The monomer molecular weight of much is approximately 0 . 5 lo6
~ daltons.
In most animal species (human, pig, and rat), mucin is in tetramer form (MW,
2x106 daltons). While pig gastric and intestinal mucin is rod shaped, rat
intestinal mucin is thread shaped.36The rate of mucin secretion in the dog
stomach is significantly higher than that in the rat.*]

G.I. capacity, fluid content, and volumes

The fluid capacities of the various sections of the G.I. tract of the various
species are given in Table 13. The holding capacities of the beagle dog stomach,
small intestine, and colon are 400-500 mL, 200-300 mL, and 200-300 mL,
re~pectively.~
In humans, under fasting conditions, the jejunum displayed an
intestinal flow rate twice that of the ileum (2.52 mLmin-' against
1.23 mL ~nin-').~*In humans, after a steak meal (the homogenized volume
of the meal was 645 mL), the volume of food passing through mid-duodenum,
proximal jejunum, and distal ileum was found to be 1500, 750, and 250mL,
respectively.6 The mean osmolalities of the fluids from the gastric, upper
jejunum, and mid/lower intestinal regions were 244,280, and 290 mosmol kgrespectively, after a meal of 232 mosmol kg-I initial osmolality.6 However,
after a milk/doughnut meal (the osmolality was 630mosmol kg-I), the
osmolalities of the gastric and the intestinal fluids were 440mosmol kg-1 and
300 mosmol kg-I, respectively.6The small bowel contents of pigs and guinea
pigs eating their usual food appears to be hypertonic compared to plasma by
30-80 mosmol kg-1.39 In humans, in the unfed state, the ionic composition
within the intestinal tract can be estimated from the ionic composition of the
gastric, pancreatic, and bile fluids.I7The gastric juice, which contains hydrogen
(4&102mM), chloride (107-140mM), sodium (19-51 mM), potassium (1417mM), and bicarbonate ( < 20mM) ions has an ionic strength of 0.1-0.165.
The pancreatic juice, which contains bicarbonate (54-1 10mM), chloride

',

366

T. T.KARARLI

Table 13. Capacities of parts of the digestive tract at autopsy. (From reference 1, with
permission)
Average absolute
capacity

Relative
capacity

(L)

(%I

Animal

Part of canal

Horse

Stomach
Small intestine
Cecum
Large colon
Small colon and rectum
Total

17.96
63.82
33.54
81-25
14.77
211.34

8.5
30.2
15.9
38-4
7.0
100.0

ox

Stomach
Small intestine
Cecum
Colon and rectum
Total

252.5
66.0
9.9
28.0
356.4

70.8
18.5
2.8
7.9
100.0

Sheep and goat

Rumen
Reticulum
Omasum
Abomasum
Small intestine
Cecum
Colon and rectum
Total

23.4
2.0
0.9
3.3
9.0
1.o
4.6
44.2

52.9
4.5
2.0
7.5
20.4
2.3
10-4
100.0

Pig

Stomach
Small intestine
Cecum
Colon and rectum
Total

8-0
9.20
1.55
8.70
27.45

31.7
100.0

Stomach
Small intestine
Cecum
Colon and rectum
Total

4.33
1.62
0.09
0.91
6.95

62.3
23.3
1.3
13.1
100.0

Cat

Stomach
Small intestine
Large intestine
Total

0.341
0.114
0.124
0.579

69.5
14.6
15.9
100.0

Monkeya

Stomach

0.1

Humana

Stomach

1-1.6

"From 10.

29.2
33.5
5.6

367

G.I. ANATOMY, PHYSIOLOGY, AND BIOCHEMISTRY

Table 14. Species variations in gastric emptying time and fecal excretion of fluid (F)
(PEG) and particulate (P) markers (2 x 2 mm). (From reference 1, with permission)
Percentage excreted in feces
(first 24 h)
Gastric emptying
half-time (h)
Species

Diet

Dog
Pig (young)

chow
high concentrate
horse diet
rabbit diet
horse diet

1.5

Pig (mature
Rabbit
Pony

2
1.3
0.3

P
1.5

10
12

Intragastric
administration
F

55
63

40
35

7
25

2
54

Intracecal
administration
F

30
7

96
2

(5&135 rnM), sodium (125 mM), and potassium (8 mM) ions, has an ionic

strength of 0.1 19-0.190. The gallbladder bile fluid containing bicarbonate

(19mM), chloride (66mM), potassium (1325 mM), and calcium (4-1 1 mM)
has an ionic strength range of 0-0534*066.
The pancreatic juice secretion rates in humans, pigs, and dogs were similar,
1-3 mLmin-.l0 The pancreatic juice of humans and common laboratory
animals contains inactive forms of the digestive enzymes: tryipsin,
chymotrypsin, elastin, carboxypeptidases, amylase, lipase, and other proteins.
G.I. MOTILITY AND TRANSIT
While the absorption of food and drug molecules from the stomach is not
considered significant, gastric emptying is an important physiological event,
which significantly influences the uptake of drug substances from the intestine.
Gastric motility has two distinct modes: the fed and unfed states. The unfed
state has several phases, which repeat every 2h.*l The intensity of the
contractions is almost zero in phase 1, intermittent in phase 2, and high in
phase 3 (housekeeper wave). Phase 3, which lasts 5--15min, empties nondigested stomach contents. Commonly used laboratory animals all display this
cyclic motility pattern.l0 When food enters the stomach, the contractions of the
stomach return to a level less than that of the phase 3 state. In the fed state,
mixing and grinding of stomach contents takes place. The size of the animal
stomach is certainly a limiting factor in the passage of non-digestible particles
through the pyloric valve into the duodenum. In humans, small and mediumsize (up to 7mm) particles and fluid can leave the stomach in the fed state.
However, large particles can be retained in the stomach for more than 12h.40In
rabbits, 11 mm enteric-coated barium sulphate tablets were retained in the

PIG

Figure 3. Passage of fluid (closed bars) and particulate matter (open bars) through the digestive tracts of the dog, pig, and rabbit. The sizes of the
particulate markers were 2 x 5 mm in the rabbit and 2 x 10mm in the dog and pig. Dogs were fed with a conventional meat diet, pigs were fed pelleted, lowconcentrate-high-fiber diet, and rabbits were fed a conventional pelleted rabbit diet. From reference 1, with permission

7m

121
1.5

0.49
150

Numbers 1, 2, etc. refer to different studies (see reference 49).

Total lipid/protein
Phospholipid/protein (pg/mg protein)
Neutral lipid (pg/mg protein)
Glycosphingolipid (pg/mg protein)
Cholesterol (pg/mg protein)
Cholesterol/phospholipid (mol mol- l )

Chick

0.54 0.41
270
205
97
165
66
85
0.5
1.22

Pig

90
1.2

150
110

3
0.6
133
119
351
85
1.26

Rat

0.56
191
195
168
80
0.87

4
0.5
190
160
209
50
0.5

60
0.74

0.43
168
104

Rabbit

0.65
131
110
403
77
1.14

0.63
128
93
207
89
1.39

0.62
160
105
290
91

Mouse

Table 15. Lipid composition of brush border membranes from different species. (From reference 49, with permission)

5
$

5
$

9
?

370

T. T. KARARLI

stomach for a 24 h study period while I mm diameter granules were partially

released during the same period.41
Table 14 and Figure 3 show the G.I. transit of fluid and particulate markers
in dogs, pigs, rabbits, and ponies. The fluid marker was most rapidly released
from the stomach of the pony and least rapidly from the stomach of the pig
and the rabbit. Dogs and pigs showed the most rapid transit from the G.I. tract
and the rabbit showed the slowest. In rabbits, particles were retained longer in
the stomach and fluid in the cecum. In adult pigs, particles were retained in the
stomach and fluid in the large intestine. The G.I. transit in young pigs was
considerably faster compared to adult pigs.
The small-intestine transit time in man is about 3-4 h and is not affected by
the presence of
There appears to be a gradient of velocity in the small
intestine. In the human and the rat, the small-intestinal transit in the proximal
intestine was faster compared to the distal i n t e ~ t i n e .The
~ ~ total
, ~ ~ G.I. transit in
humans is around 2&30 h.21 Beagle dogs have substantially shorter transit
times, 6-8 h.21
The G.I. transit times in the rat and the guinea pig were compared by
administering 1251-PVPintraduodenally." After 20 min, the isotope peak was
found in the ileocecal region in the guinea pig whereas 50% of the isotope had
passed through half of the small intestine in the rat. In the rat, the stomach
emptying of 75% of the 1311-PVPwas complete in 15mi11.~5
The transit time in the human colon can vary from 8 to 72 h. In humans, the
transit of liquids and solids from the ascending colon was around 5 h.46The
transit of "lIn pellets through unprepared colon was quantitated by Proano et
u I . They
~ ~ found that 12 h after ingestion, 59% of the particles were recovered
in the ascending colon and 21% in the transverse colon. By 24h, counts were
distributed between all sections of the colon. By 48 h, 56% of the counts had
been excreted and 30% remained in the transverse colon. The ascending and
transverse colon appear to be the sites for storage, whereas the descending and
retrosigmoid function mainly as conduits. The rate of digesta marker passage
through the large intestine of the dog, pig, and pony seems to be related to the
relative length and degree of sacculation of the colon.'

BIOCHEMICAL CONSIDERATIONS
Lipid composition of the brush border membrane

Passive, active, facilitated, and pinocytotic uptake mechanisms for nutrients

and drugs across the intestinal membrane are greatly influenced by the lipid
composition of the brush border and basolateral membranes of the enterocyte.
Therefore, any species differences in the relative composition of the
phospholipids, glycolipids, cholesterol, and free fatty acids of the enterocyte
membranes can alter the rate and extent of drug uptake from the G.I. tract. In

Numbers 1, 2, etc. refer to different studies (see reference 49).

38.3
32.6
13,O
8.7
6.4

34.0
34.0
12.0
10.0
10.0

Phosphatidylethanolamine
Phosphatidylcholine
Phosphatidylserine
Phosphatidylinositol
Sphingomyelin
Lysophosphatidylethanolamine
Lysophosphatidylcholine
Phosphatidic acid
Cardiolipin
Phospho tidylglycerol
1.0

Pig

Phospholipid
37.4
26.8
11.2
6.4
7.0
6.9
4.3

8.7
0.9

11.9
26.7
4.4
22.3
24.1

Rat

0.5

2.8
4.0
2.5
2.6
1.4

8.0

6.7
1.7

28.4
36.4
6.8
7.4

39.5
20.7
14.0

2
47.2
20.6
13.3
5.6
7.3
2.8
3.4

1
30.3
35.0
7.5
8.3
10.5
3.6
3.1
1.2

Rabbit

Percentage of total phospholipid

2

11.6

49.1
25.1

Mouse

61.7
16.2
14.2
7.9

Table 16. Phospholipid composition of brush border membranes from different mammalian species. (From reference 49, with permission)

cb

%
5

372

T. T.KARARLI

the passive diffusion mechanism, a drug molecule has to be solubilized in the

lipid matrix before it can diffuse into the cytoplasm. Carrier or active transport
processes require specific transport proteins on the brush border membrane for
uptake, and here the lipid-protein interaction and the membrane fluidity can
greatly influence the activity of these protein molecules. For endocytotic or
fluid-phase pinocytotic absorption mechanisms for large molecules, the fluidity
of the membrane can be critical.48
Proulx has provided an excellent review on the structure-function
relationship in the intestinal brush border of various animal species.49Tables
15 and 16 give the lipid and phospholipid compositions of the brush border
membranes from the chick, pig, rat, rabbit, and mouse. The total lipid to
protein ratios in the chick, pig, rat, and mouse microvilli membranes are
similar (O.SO.6). Phosphatidylcholine and phosphatidylethanolamine account
for 60-70% of the lipids in all species. In the mouse and rabbit,
phosphatidylethanolamine is more abundant than phosphatidyl~holine.~~~~*
The cholesterol/phospholipid ratio appears to be the lowest in the pig and
rabbit microvilli membranes (Table 15).52,s3
The microvillus membrane compared to the basolateral membrane contains
a higher cholesterol/phospholipid ratio, a lower lipid/protein ratio, and a
higher glycosphingolipid content (Table 16).54,5s In the rat and rabbit,s4-58
brush border membranes have a high degree of acyl chain saturation, but not
in mice.59This along with the higher glycolipid content leads to reduced fluidity
for the microvillous membrane compared to the basolateral membrane.49-ss
Besides diacyl derivatives, the phospholipids of rabbit small-intestinal brush
border membrane comprise plasminogen and alkylacyl subcla~ses.~~
In the
mouse, rat, and rabbit microvillus membranes, the major glycosphingolipid
In the pig, digalactosylceramideand
consists of monohexosylceramide.50~s3~60~6
pentahexosylceramides2 are the major components. In rat microvillus
membranes, the monohexosylceramide fraction contains glucose as a sugar
constituent6] whereas in pig membranes, both glucosylceramide and
galactosylceramide are present.52 The lipid phase transition in the rabbit
membrane compared to that of the rat is 10C higher.49
The lipid composition of the microvilli changes along the length of the small
intestine and the colon. Compared to the proximal segments, the distal
segments display an increased content of cholesterol, a greater cholesterol/
phospholipid ratio, and a higher degree of saturation in the phospholipid acyl
side ~ h a i n s . ~In
~ pigs,
J ~ the
~ cholesterol/phospholipid ratio of the microvillus
membranes of the jejunum are higher compared to those of the duodenum.64
The same trends were also observed for the crypt cells as they mature and
migrate to the villus tip.62
The age of the animal can also lead to different lipid c o r n p ~ s i t i o n . ~ > ~ ~ , ~ ~
Microvillus membranes from the jejunum and ileum of suckling rats were
reported to display a higher sphingomyelin/phosphatidylcholineratio and were
richer in total lipid, cholesterol, and phospholipid per milligram of protein than

aAngiotensinconverting enzyme.
b'Folate conjugase'.
'PABA peptidase.
dVariable,dependent on species.
Where possible reference has been made to human data.

Unknown
Regulatory

Phosphatase

Peptidase

Maltase-glucoamylase

Glycosidase

Sucrase-isomaltase
Lactase-phlorizin hydrolase
Trehalase
Aminopeptidase A
Aminopeptidase N
Aminopeptidase W
Carboxypeptidase P
Dipeptidyl aminopeptidase IV
Peptidyldipeptidasea
Pteroyl polyglutamate hydrolaseb
Enteropeptidase
Endopeptidase 24.11
Endopeptidase-2c
y-glutamyl transferase
Alkaline phosphatase
Phosphodiesterase-I
'140 kDa glycoprotein'
Guanylate cyclase
Phospholipase A,

Protein

Function

140

330/125+ 135d
145+151
160 ( x 2)
80 ( x 2 )
170 ( x 2 )
162 ( x 2)
130
130
136 ( x 2)
180
91
300d
96 ( x 2 )
100 ( x 2)
62 + 21
86 ( x 2 )

Molecular
mass
(kDa)

+
+
+
+
+
+

+
+
+
++
+
+

Carbohydrate
content

+
+

+
+

DNA
sequence

+
+

Primary
deficiency

0.1

0.1-ld

<0.1

0.2

10

("/I

Abundance

Table 17. Brush border enzymes and related proteins of the microvillus membrane. (From reference 67, with permission)

W
4

.e

t3

$E

0
"4

"5

n
?

374

T.T.KARARLI

Table 18. Major transport functions of the brush border. (From reference 67, with
permission)
Substrate(s)
Monosaccharides
Amino acids

glucose
galactose
fructose

acidic
glutamic acid
neutral
alanine
basic

Peptides
Fatty acids
Bile salts

Vitamins

Ions

lysine
imino
proline
phenylalanine
dipeptides
long-chain oleic acid
such as taurocholate
ascorbic acid
biotin
folic acid
inositol
pantothenic acid
thiamine
Ca2+
F$+, Fe3+
Na+/H+
Cl-/HCO,phosphate, sulfate

Na+ dependence

Primary
deficiency

+
+
+
+
+

?
?

+
+
+
+
+
+
+

Hartnup
Cystinuria

+
?

+
+

their counterparts from postweaning rats. The molar ratio of saturatedlcisunsaturated fatty acids and the cholesterol/phospholipid ratio increased
significantly from the natal to the suckling p e r i ~ d . ~ ~ , ~ ~
The observed differences in the membrane composition of the enterocytes
may contribute to (i) variable drug absorption from the different regions of the
gastrointestinal tract, (ii) different rate and extent of drug absorption as a
function of the age of the same animal, and (iii) species differences in oral
bioavailabilities.
Protein content of the brush border membrane

Brush border membranes contain a number of characteristic hydrolytic

enzymes and transport systems. The enzymes of the brush border are
important in the hydrolysis of oligopeptides and oligosaccharides. The
transport systems are utilized for the uptake of nutrients, which may be
coupled to N a + cotransport. To date, over 22 enzymes and 19 transport or

G.I. ANATOMY, PHYSIOLOGY, A N D BIOCHEMISTRY

375

binding functions have been localized to the brush border membrane.67Some

of the identified enzymes and active and carrier transport proteins are listed in
Tables 17 and 18, respectively. The differences in the quantity and location of
the protein make-up of the microvillus membrane varied among animal species
would contribute to variable transport and metabolism for some molecules.
OTHERS
Peyer 's patches

Peyer's patches (PPs) are the collections of lymphoid follicles distributed

within the lamina propria and submucosa of the small intestine. The PPs are
separated from the gut lumen by either a single layer of so called M cells or a
combination of M cells plus normal columnal cells. PPs perform a central role
of antigen uptake and induction of immune response.
The number and location of PPs varies between mammals but the basic
morphological structure is similar. Generally, the number and the size of the
PPs increase with age, body weight, and length of the small intestine. In mice,
six to 12 PPs are distributed along the entire small intestine and the size of each
patch varies depending on the number of lymphatic nodules aggregated. Small
patches contain only two to three nodules, larger patches contain seven to nine
nodules and are 1.3-3-Omm long.9 In the New Zealand white rabbit, the
number of patches increases from the proximal small intestine to the ileum.68
There are no patches in the newborn animal, but patches are apparent on day
15. The number of PPs in healthy adult animals varies from two to 10 with a
~*
mean of four. The average size of the PPs was recorded to be 7 x l O m r ~ . In
many species, including ruminants, such as sheep and calves, omnivora, e.g.
pigs, and carnivora, e.g. dogs, there are several discrete patches in the jejunum
and upper ileum and a long continuous patch in the terminal ileum. In pigs,
there are a series of 20 long, disk-like discrete patches in the small intestine with
an average size of 3-8cm.69,70
There are 10 irregular-shaped, large patches in
the first 20cm of the spiral colon and one continuous ribbon-like PP in the
ileum running from the ileocecal junction for 1 to 3 m and occupying 15% of
~ ~ 1the small intestinal length.69~70
In sheep, there are a total of 3O-40 P P s . The
2m long ileal patch covers most of the circumference and accounts for 17% of
the length of the small intestine and 1YOof the body weight of a two-month-old
lamb. In the dog, there are a total of 2 6 3 9 PPs, which are randomly
distributed with a large variation between the individual dogs, except for the
first four or five patches in the proximal duodenum and the single patch in the
ileum.72The long ileal PP of the dog begins proximally as a band 10 mm wide
at the antimesenteric side of the ileum. After 100-14Omm the band gradually
becomes broader and involves the entire circumference of the ileum over the
distal 65-105mm. The PP ends at the ileocecal junction.72 In humans, the
number of PPs containing more than five follicles varies from 59 before 30

376

T. T. KARARLI

weeks gestation to 239 at puberty. The number of large patches containing

more than 25 follicles varies from over 40 at term to 100 or more at p ~ b e r t y . ~ 3
In general, the ileum contains larger and more numerous patches than the
jejunum. However, some subjects may contain smaller but more numerous
patches in the jejunum than in the ileum. The longest human patch observed in
the ileum measured 9.9cm in length.73
In humans,74
dogs,76 monkeys,I3 and pigs77 the epithelium
covering the domes of PPs contains a combination of enterocytes and
microfolds or so-called M cells. M cells have multiple vesicles, suggesting a
transport function for luminal antigens.74Pig M cells contain densely packed,
long, thick and irregular-shaped m i ~ r o v i l l i .Rat
~ ~ M cells display irregular
microvilli that are shorter and broader than those of the adjacent absorptive
cells.75Human M cells are covered by irregular ridges or microfolds instead of
m i ~ r o v i l l i .The
~ ~ rabbit M cells also contain microvilli with small fibrous
extensions running into the cytoplasm.68 Monkey M cells contain coarse,
irregularly spaced m i ~ r o v i l l iIn
. ~ calves,
~
the domes are covered primarily by M
cells, which have irregular, short, thick and densely packed m i ~ r o v i l l iIn
. ~ ~the
beagle dog, the M cells are scattered among more numerous enterocytes in
duodenal and jejunal PPs, but constitute the major cellular component of dome
epithelia of the ileal P P s . ~Dog
~ M cells are covered by fewer but slightly
thickened microvilli. The transport of macromolecules across M cells and PPs
into lymphatics has long been studied to help deliver peptides and proteins
through the oral route.79
CONCLUSIONS
In general, current data indicate that no single animal can mimic the G.I.
characteristics of humans. Therefore, human studies cannot be substituted by
animals. However, for a given purpose, selection of the right animal model is
possible. For example, dogs and humans have similar stomach morphology
and emptying characteristics. Pig and human colon morphology appears
similar. The microbial content of the rabbit intestinal microflora is similar to
that of the human. Our understanding of the species differences in G.I.
anatomy, physiology, and biochemistry is incomplete. From in vivo drug
absorption studies, it is difficult to assign the observed differences in
bioavailability to any one factor. Overall, we need more mechanistic studies
to delineate the effects of anatomical, physiological, and biochemical
differences between species on overall drug absorption.
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