3

Gastrointestinal Absorption—
Biologic Considerations

Drugs are most commonly given orally and the participation of components of the membrane. Ac-
gastrointestinal tract plays a major role in deter- cordingly. the biologic membrane may he viessed
mining the rate and extent of drug absorption. In as a dynamic lipoid sieve, a semipeinteable lipoid
this chapter, the more important biologic factors rrnihrine Containing numerous aqueous pores or
that inl 1 uence dru g absorption are considered. channels. too small to he seen, and a host of carrier
molecules that shuttle hack and forth across the
MEMBRANE PHYSIOLOGY membr anes like ferries.
Lipid-soluble molecules penetrate the harrier di-
The gastrointestinal barrier that separates the rectly through the fat-like portion of the lipoprotein
lumen of the stomach and intestines from the s 5- membrane. The aqueous pores render the epithelial
temic circulation and the sites of drug action is a membranes freely penueahle to us ater. to mono-
complex structure composed of proteins, alent ions, and to li drophil ic solutes of small
hpoprotgin, and pulysaccharidcs. The barrier has molecular size such as urea. By introducing aque-
ire characteristics of a semipeniteable membrane, ous solutions of molecules of graduated size into
permitting the rapid passage of some chemicals the human intestine, and by determining the facility
hile retarding or preventing the passage of others. of absorption, it has been estimated that the. hy-
Amino acids, sugars, fatty acids, and other nutri- pothetical pores in the proximal intestine tjejunum)
ents required for life readily cross the barrier in the have all average radius of 7.5 A (7.5 x l mm)
healthy individual. At the same time the barrier can and those in the distal intestine (ilcum), one of
be highly restrictive. For example, there is virtually
about 3.5 A) The molecular size of most drug
no leakage of plasma protein into the gastrointes-
molecules suggests that pore. transport is of minor
tinal tract its the healthy mammalian adult. Certain
i mpoilance in drug absorption.
toxins, which would produce lethal effects if pres-
The digestive end products of dietary carbohy-
ent ill circulation in minute quantities, are harm-
tlrales and proteins are hexose and amino acid mul-
less if ingested because of their inability to traverse
ecules that are water soluble but usually too large
the harrier. Most drugs used in clinical practice are
to flow easily through the system of pores. The
administered orally and must cross this barrier be-
carriers in the membrane transport these water-sol-
fore reaching the systemic circulation. Thus, the
uble substances through the lipid, perhaps by in-
characteristics of the gastrointestinal barrier are of
considerable importance in biopharmaceutics. teracting with the solute to render it temporarily
Lipid-soluble molecules as well as small, by- fat soluble.
drophilic molecules and ions are readily absorbed Meiitbrane transport of dru s and other che ii-
from the gastrointestinal tract in an apparently pas- cals direct y t truuh the lipid or ilqtieotts chwie1
sive manner. Certain larger polar molecules with
molecular weights up to several hundred are also
absorbed but i n a manner suggesting the active or, in some Cases, mitre transport.'
 Gastrointestinal Ab%orplion—lli olagic Considerations 25

Carrier-Media ted Transport

Passive Diffusion
mciii- • Although most drugs are absorbed from the gas-
The transfer of most drugs across boIogic trointestinal tract by passive diffusion, certain coin-
lanes occurs by passive diffusiot) from a region
pounds of therapeutic interest and many substances
of higher concentration to one of lower concentra-
of nutritional concern are absorbed by an appar-
tion. Passive transport is described by Ficks first
law which states that the rate of diffusion acios. a ently carrier-mediated transport mechanism.
Active absorption takes place when the intestine
on each side of on'
the rnemrae_ transports a substance uphill against a concentra-
lini^ rug
tion gradient. This phenomenon is easily demon-
ctraub0n
strated by placing identical solutions of glucose on
kC = k(C either side of an excised segment of intestine. After
a while, if the segment is kept viable, the concen-
where C 1 and C. denote the drug concentrations on
each side of the membrane and k is a proportion- tration of glucose is found to be decreased on the
ality constant. By convention, we assume that mucosal (lumen) side, whereas its concentration on
the serosal side has increased over the initial level.
C 1 > C2 and that there is net transport of drug from
region 1 to region 2. The proportionality constant The epithelial cells have apparently pumped glu-
incorporates the diffusion coefficient of the drug, cose uphill. Facilitated diffusion takes place when
the thickness and area of the biologic membrane, the intestine transports certain solutes downhill but
and the permeability of the membrane to the spe- at rates much greater than would be anticipated
based on the polarity of the solute and its molecular
cific drug.
The gastrointestinal absorption of a drug from size.
an aqueous solution requires diffusion in the lumen Acti'e or facilitated absorption is usually ex-
to the gut wall and penetration of the epithelial plained by assuming that carriers in the lipoprotein
barriers to the capillaries of the systemic circula- membranes of the intestinal epithelial cells are re-
tion. Upon emerging in the blood, the drug dis- sponsible for shuttling these solutes in a mucosal-
tributes rapidly into all volume that is to-serosal direction. The major substances that are
usually considerably larger than blood volume. believed to be actively transported are sodium.
Thus, during absorption, drug concentration in the other ions such as calcium and iron, glucose, ga-
blood will be much lower than at the absorption lactose, amino acids, bile salts, and vitamin B1..
site. In essence, the general circulation functions A larger number of substances, including other vi-
like a sink for the drug in the gastrointestinal tract. tainins, such as riboflavin and thiamine, and cin
and a large concentration gradient is maintained drugs, are believed to be absy facilitated
throughout the absorption phase; that is. 1.
The number of apparent carriers in the intestinal
C >> C2 . Consequently, the concentration gra-
membranes is limited. Therefore, the rate of car-
dient (SC) is nearly equal to C 1 . and Equation 3-1
may be rewritten as rier-mediated transport must be described by the
following equation:
-dC/dt k C 1(3-21
which is the familiar form of a first-order rate equa- Absorption rate Y ­C (33)
tion. -- - --
The gastrointestinal absorption of most drugs where C is the solute concentration at the absorp-
from solution may he described by first-order ki-
tion s iT an are 0fl stants. At lo
netics; the rate of absorption is proportional to drua 'iute concent ra tio ns , suTThfl>C,
concentration over a wide concentration range in-
dicating passive absorption. For esample, the ab- C (3-4)
Absorption rate = -' C
sorption rate of hydrocortisone from the human
small intestine is proportional to the concentration
and apparent first-order kinetics are ohsers'ed. Un-
of the drug over a 2000-fold concentration range
der these conditions there are a sufficient number
(from 0.05 to 100 mgIL). 2 The passive absorption
process is driven solely by the effectise concen- of carriers so that it constant proportion of solute
molecules presented to the epithelial surface is'
tration gradient that exists across the gastrointe'
transported. As the solute concentration increases
final barrier.
 26 Itiot)har:n;Ic(.Il(ics ;irid (Iiriial F'hiir,nacr.,kiiivi i

The amino acid system is specific and strongly

fin ors the transport of the L- stcrcoi Soilteric f mu
as opposed to the Dform of amino acids. The
0 hesose system requires the Particular molecular
0. configuration of lucosc a wide variety of other
0
U,
6-carbon su g ars are unacceptable to the carrier. In-
dependent carrier- mediated processes have been
identified for the absorption of bile salts and py-
0
rim dines.
a)
C Competition betcr i two similar substances for
the same tr.snsfer mechanism and inhibition of ab-
sorption of one or both compounds are other char-
acteristics of canier-mediated transport Inhibition
of absorption may also he observed with agents,
such as sothum fluoride, cyanide, ordinitrophcnn],
that interfere with cell nictabolismn.
Drug Concentration at Absorption Site If the stricture of a drug is sufficiently similar
to that of a substance absorbed by carrier-mediated
Fig. 3-1. Pelatonship between absorpticn rate and drug
concentration fcr a passive process (curve A) and a carrier- transport. there is the likelihood that the drug may
mediated process (curve B). also be absorbed in this manner. Methyldopa and
Icuodopa are both absorbed by active transport via
an amino acid transport mechanism, Penicillamine,
the number of unoccupied carriers is reduced and
all acid analog used i.n the treatment of Wil-
the prOportion of solute molecules that actually gets
son's disease and lead poisoning, is actively trims-
across the membrane declines until a maximum
poried across the rat intestine.' Uphill transport is
absolute number is reached. When C >> K 0 . then
found with the L-isomer but not with the D-fomi.
Absorption rate V,., (3-5) Active tran s port of penicillamine is decreased in
the presence of cyanide and certain L-amino acids.
Further increases in solute concentration are not
Serinc and threonine derivatives of nitrogen meic-
associated with any increase in the rate of asorp-
tard, which have heeti investigated for antitumor
ion.
activity, are also absorbed by a carrier-mediated
Absorption rate-concentration relationships for
process.' Another antitumor agent, 5-fluorouracil,
carrier-mediated and passive diffusion processes is actively transported across the small intestine by
are shown in Figure 3—I. The plot describing the the pyrimidine transport system-'
passive process is linear over the entire concentra- Some substances may be absorbed by simulta-
tion, range (see Eq. 3-2). The absorption rate of a
neous carrier-mediated and passive transport proc-
substance that is transported by active absorption esses. Certain pyrimidines such as uracil and thy-
or facilitated diffusion shows linear dependence on mime are a case in point . 6 The contribution of each
concentration only at low concentrations (see Eq.
process to the total absorption rate varies with con-
3-4). As the concentration increases the rate of centration. The contribution of the carrier-ttmediated
ascent of the Curve decreases, and eventually the
process to the overall absorption rate decreases
absorption rate becomes invariant with concentra- with concentration and at sufficiently high concert-
lion (see Eq. 3-5). The plateau region of the curve
trzitiuns is negligible.
reflects saturation of the carrier mechanism. This
The capacity-li niitcd characteristics of carrier-
type of rate process is termed a capacity-limited
mediated processes suggest that the bioavailability
process.
of a drug absorbed in this irtanner should decrease
There appear to be several carrier-mediated with increasing dose. Figure 3-2 shows that the
transport systems in the small intestine. Each is
relative availability of riboflavin in man decreases
characterized by both structural and site specificity.
with increasing amounts of administered vitarnin.7
For example, amino acids and monosaccharides Above a certain dose, the amount of riboflavin
such as glucose and galactose are absorbed in a
absorbed remains constant regardless of lIme size of
specialized fashion but by different carrier systems.
the dose. Similar findings are reported for thiamine
 27
Gastrointestinal Absorptto I1 _1tiOtOglC Considerations

in the stomach tinder experimental conditions. Eth-

5° anol is rapidly and completely absorbed from the
ligated stomach pouch of the dog. Similar findings
40 with sulfaethidole and barbital have been reported
0
0 in surgically altered rats)° However, under normal
' 30
conditions, when gastric emptying is not impeded,
0 the stomach's role in drug absorption is modest.
20
The absorption of aspirin and ethanol from the
0 I human stomach after oral administration of aque-
ous solutions to healthy subjects has been estimated
0.
0 15 zu to he about 10 17- and 30% of the dose, respec-
Dose (mgI tively.°° In each case, the balance of the dose is
absorbed from the small intestine.
Fig. 3-2. Relative bioavaitability of riboflavin (expressed The small intestine is the most important Site for
as percent of dose) as a function of oral dose administered drug absorption in the gastrointestinal tract. The
to lasting subjects. (Data from Len, G., and Jusko, Wi.')
epithelial surface area through which absorption
can take place in the small intestine is extraordi-
and ascorbic acid. 89 The use of large single oral narily large because of the presence of villi and
doses of these vitamins is irrational. If relatively microvilli, linger-like projections arising from and
large daily doses are required. one should use di- forming folds in the intestinal mucosa. The irreg-
vided doses. ularities in the mucosal surface caused by the mi-
crovilli, villi, and submucosal folds increase the
GASTROINTESTINAL PHYSIOLOGY
area available for absorption by more than 30 times
The major components of the gastrointestinal that which toukt be present if the small intestine
tract are the stomach. small intestine, and large
were a smooth tube- 13 Based on studies in the rat,
intestine or colon (Fig. 3-3). The small intestine one can, estimate that the effective surface area of
includes the duodenum, jejunurn, and ileum. The the, small intestine is about 10 times that of the
major segments of the gastrointestinal tract differ
stomach. 11 Other studies conclude that surface area
from one another both anatomically ar.d morpho-
decreases sharply from proximal to distal small
logically, as well as with respect to secretions and
intestine. The surface area in man has been esti-
PH.
mated to range from 80 cm 7lcin serosal length just
The stomach is a pouch-like structure lined with
beyond the duodenojejunal flexure to about 20 cns/
ti relatively smooth epithelial surface. Extensive
cm serosal length just before the ileocecal valve.'
absorption of weakly acidic or nonionized drugs
There is also a progressive decrease in the average
and certain weakly basic drugs can he demonstrated

Stornh
( p9 1 to 3)
rode- -
(ph 5

AscedvZ

(p ,i 7 to 8

Fig. 3-3. Representation of the hurrarr gaxtrointestinal tract.

 28 13 itpItii rn,iicc itiIS and Clinical that tita._' hi at i(

Si/C of aqueous pores from proximal to distal small dose of a drug that is gic cit orally irul coritpletely
intestine and colon. ahst ched i expowd to I lie is ci before reachingg
The small intestine is also the most important the blood.s :ream . Soi-e the liver is the most i in-
region of the gastointestinal tract with respect to port tnt orca n in the bod y for drug mmmctabol is m and
carrier-mediated transport. The proximal small in- irtetahol itc- some drugs J1y there is the pos-
testine is the major area for absorption of dietary stbiltty tha: a large fraction of the dose will never
Constituents including monosaccharides, anilno reach the -\ sternic cirsul;itton bcausc of liepatie
acids, vitamins, and minerals. However, both vi- ttletaholist: during ahsorptton. This phcnotiicnoit
tamin 8 )2 and bile salts appear to have specific is knowns the hepatic fir s t-pass effect and is re-
absorption sites in the ileum. 5 sponsible r the lcss-than-coniplete hioav;iilahility
The large intestine, like the stomach, has a con- of many dJgs given orally. Metabolism of i t drug
siderably less irregular mucosa than that of the during ab. rptton bs en/N toes found in the gut ss all
small intestine. This segment serves its a reserve may also :ditcc bioavailahtlity. A more detailed
area for the absorption of drugs that have escaped discussion o f these aspects of drug metabolism is
absorption proximally because of their physio- presented n Chapter S.
chemical properties or their dosa g e form en-
teric-coated tablets and sustained - release prod- jIointestinai pH
ucts). The large intestine is no an ideal absorption There ma y he as much as a 10 million-fold dif-
site, however, and incomplete absorption may re- ference in ..ydrogen ion concentration between the
sult if a large fraction of the dose of a drug reaches stomach ard the colon. An exceedingly abrupt, 10
the colon. On the other hand, the large intestine thousand-i.id difference in h y drogen ion concen-
may play an important role in the efficacy of orally tration cxis beta ccii the stomach and the duo-
administered drugs, such as sulfasalaiine, that re- denum. Tr .m pH at the absorption site ,is an itripor-
quire metabolism (reduction) by intestinal bacteria taut factor :n dru g ahorptton because many drugs
in t ileum and colon for hioaetivation. are either '. eak or g anic acids or bases. In solution,
organic cletrolvtes exist in a nortioniied (usumtllv
asiroinfes
Z final Blood Flow
lipid-solubm) and an ioniied iusually poorly lipid-
The blood perfusing the g astrointestinal tract soluble) fo:m. The fraction of each species depends
plays an important role in drug absorption by con- on the pH of the solution. Since the gastrointestinal
tinuously maintaining the concentration gradient harrier (as well as many other barriers andoem-
across the epithelial membrane. The dependence branes in the body) is much more permeable to
of intestinal absorption on blood flow rate changes uncharged. lipid-soluble solutes, a drug may be
from blood flow-independent to blood flow limited well absorbed from one segment of the gastroin-
as the absorbability of the substance increases.'' testinal tract, where a favorable p11 exists, but
Polar molecules that are slowly absorbed show no poorly absorbed from another segment, where a
dependence on blood flow; the absorption of lipid less favorable pH is found. The absorption of
soluble molecules and molecules tha t are small weakly basic drugs such as antihistamines and an-
enough to easily penetrate the aqueous pores is tidepressants is favored in the
tFi small intestine where
rapid and highly dependent on the rate of blood such drugs exist lareely in a nonionized form. On
flow. The absorption rate of most drugs probably the other hand. the acidic gastric fluids tend to
shows an intermediate dependence oil tlosv retard the absorption of weak bases but promote
rate; relatively large decreases from normal tiles- the absorption of sscakly acidic drugs such as sul-
enteric blood flow rate are required to produce an fonamides and nonste roidirl atit i-i tiflani mat ones -
important change in absorption rate. In general, the Changes its the p11 of the fluids in a given segment
rate of drug absorption is unaffected by normal of tract may improve or impede the absorption of
variability in mesenteric blood flow. Ordinarily, a drug.
changes in mesenteric blood flow thaE result from The pH of gastric fluid varies considerably. Gas-
disease or drug effects must be substantial and sus- tric secretions have a p1l of less than I. but the pH
tained to significantly influence drug absorplioti. of gastric contents is usually between I and 3 be-
The entire blood supply draining mo s t of the cause of dilution and diet. The p11 of the stomach
gastrointestinal tract returns to the systemic Cir- contents is distinctl y but briefly elevated after a
culation by way of the liver. Therefore, the entire meaL 141 ahites of 5 .,re tot unusual. Fasting tends
 29
Gastrointestiflt Absorption—! otngtc Coustderatiolls

luteal phase of the menstrual cycle. Many drugs

to decrease the pH of gastric fluids. Disease may
including atropine and propanthelille, narcotic an-
also influence the pH of the stomach. The average
algesics, amitniptyl inc. imipranline, desipraminc,
gastric pH is significantly lower in patients with a
chlorpromazine, and aluminum hydroxide can also
duodenal ulcer than in healthy individuals. Fats and
retard gastric emptying,.yropantheline has been
fatty acids in the diet have been found to inhibit.
found to double the mean gastric half-emptying
gastric secretions. A major clinical effect of anti-
time of a test meal in After placebo the
spasmodic drugs, such as atropine and propanthe-
mean half-emptying time was 68 mm and after 30
line, and 1-1,-blockers, such as cimetidine and ra-
mg of propantheline bromide it was 135 ruin as—
itidine, is a reduction in gastric acid. Some
tric emptying is promoted by fasting or hunger,
nticholinergiC activity, including suppression of
alkaline buffer solutions, anxiety, lying on the right
gastric secretions is commonly found with many
side, diseases such as hyperthyroidism, and drugs
other drugs. Antacid It roCtS are widely used for
such as ructoclopramide a dopaminergic blocker,
the purpose of neutralizing gastric acidity and el-
Widely used for nausea and vomiting associated
evating the pH of gastric contents. Disease or drug-
with cancer chemotherapy/
related changes in gastric pH may influence the
Gastric emptying of liquids is much faster than
dissolution, stability, and/or absorption of ceriain
that of food or solid dosage forms. It has been
found in normal subjects that complete gastric emp-
7TRlC. EMPTYING AND tying of enteric-coated barium granules, adminis-
GASTROINTESTINAL MOTILITY tered in a standard breakfast, requires about 4 to
8 hr.° When considering the emptying of a single
/ In theory, weakly acidic drugs should be better
object from the stomach, such as an enteric-coated
absorbed from the stomach than from the intestine,
tablet, terms such as half-life are meaningless.
because a larger fraction of the dose is in a non-
Emptying of a single unit is a random process.
ionized, lipid-soluble form. However, the limited
Intact tablets have been observed in the stomach
residence of the drug in the stomach and the rel-
as long as 6 hr after ingestion of an enteric-coated
atively small surface area of the stomach more than
product with a meal .°
balance the influence of pH in determinin g the op-
Gastric emptying is one of the more important
timal site of absorption. Thus, factors that promote
factors contributing to the unusually large inter-
gastric emptying tend to' increase the absoptiofl
subject variability in the absorption of drugs from
rate of all drugs. The converse is also true. Slow
enteric-coated tablets. As a means of reducing this
gastric emptying can delay the onset ofeffect of
variability. it has been suggested that enteric-
drugs such as analgesics or sedatives jr. situations
coate medication
d be administered in the form of
requiring prompt clinical response. Prompt gastric small, individually coated granules that would
emptying is important for drugs that ae unstable
empty gradually but continuously into the duode-
in stomach fluids because of low pH or enzyme
activity. For example, the extent of degradation of num)
penicillin G after oral administration depends on Differences in gastric emptying among patients
also contribute to the variability in absorption rate
its residence time in the stomach and on the pH of
of drugs from conventional dosage forms For ex-
the stomach fluids./
ample. after administration of 1.5 g (3 tablets) acet-
Gastric emptying often appears to he an expo-
aminophen to 14 convalescent hospital patients the
nential process. Standard low bulk meals and liq-
maximum concentration in the plasma ranged from
uids are transferred from the stomach to the duo-
7.4 to 37.0 p.gimnl. and the time required to reach
denummi in an apparent first-order fashion with a
the maximum concentration ranged from 30 to 180
half-life of 20 to 60 ruin in the healthy adult. How-
ever, ma,py factors call the rate of this mis) 2 Both these indices of absorption rate
linearly telitd to the gastric emptying half-life
process/Gastric emptying is retarded by fats any
found4) in each patient (Fig. 3- . Despite the
fatty acidiii the diet, high concentrations of dec
marked variability in absorption rate, little differ-
trolytes or hydrogen ion, high viscosity or bulk
ence in the extent of absorption of acetanminopheil
mental depression, lying on the left side, disease:
was found among patients. A similar correlation
such as gastroenteritis. pyloric stenosiS, gastril
between absorption rate andgastric emptying has
ulcer, gastrocsopliageal reflux, Crohns disease
celiac disease, and hypothyroidism and during th e been observed ill 012111 With cinietidinc-21
30 Iliepharinaceulics and Clinical Ph irmai;kturt ks

E and stay there until it disintegrates. This may cause

damage to the ccophagcal mucosa, leading to ul-
4°
ceration and later to stricture or perforation.
Esophageal ulceration has been described for
30 0 many drugs including aspirin and other nnnsteroi-
I—
z dal anti-inflammatory drugs (NSAIDs). slow-re-
Si 0
0 lease KCI. tetracycline, doxycycline, clindainycin,
z 20 0
0
0 0 quinidine. and iron salts. One case report 25 cites a
z patient with mild asthma who on one occasion,
Ld 0 0 '0
I tO after forgetting to take the evening dose of slow-
0 0
release theophylline, swallowed his medication
1
without v. atcr '.shen he went to bed. The tablets
20 40 - 60 80 tOO seemed to lodge in his esophagus; he ignored this
Si
0 GASTRIC EMPTYING HALF — TIME. mm . sensation. swallowed several times, and went to
4
sleep. On awakening, the patient experienced se-
Fig. 3--4. Relationship between peak concentration of vere, sharp retrostemal pain; this persisted for 2
acetaminophen in plasma and gastric emptyng Call-time weeks. A large local esophageal erosion was iden-
alter a single oral dose. Rapid gastric emptying results in
tifiedn eophagoscopy and the patient was treated
hgh peak levels. Data from Heading, R.C., et al.;')
with hour l y antacids; symptoms resolved within
one week.
Posture, which affects gislric emptying, also af-
Slow esophageal tsansi also delays drug ab-
fects the absorption of acetaminophen)' Accla- sorption. Twenty patients awaiting cardiac cathe-
iiiinophen absorption was markedly delayed in all
terization swallowed a single tablet containing acet-
subjects lying on the left, side compared to. that
aminophen and barium sulfate. The first 11 subjects
observed when the same subjects were ambulatory
swallowed the tablet with up to IS ml water while
(Fig. 3-5). This effect must be taken into account
supine: the tablet's progress down the esophagus
in drug absorption studies conducted in hospital- was folh.ved by fluoroscopy. In 10 of these sub-
ized patients.
jects, transit of the tablet was delayed in the esoph-
Tablets and capsules are commonly swallowed
agus. The 9 subjects who followed, swallowed the
with little or no water and many patients in bed
tablet while standing; in all cases, it entered the
swallow them lying down. Under these conditions,
stomach immediately)6
a solid dosage form may lodge in the esophagus
The mean peak plasma concentration of aceta-
minophen in the patients who experienced no
esophageal delay was 8.8jig/nil and the median
time to peak was 35 mm, whereas mean peak con-
centration was 5.9 jag/nil and median time to peak
20
was 105 min in those where tablet transit was de-
layed in the esophagus. When there is delayed
Ii esophageal transit, absorption in the first 60 mm
C
a is much less than when normal transit occurs.
a
. 10 Patients should be advised that tablets and cap-
sides must be taken with several swallows (at least
0)
'a 2 ounces) of water or other beverages, while stand-
ing or sitting upright. This is particularly important
for drugs that may damage the esophageal mucos-a
or that need to be absorbed rapidly to induce sleep
time, min or relieve pain.
On the basis of aspirin absorption studies, it has
Fig. 3-5. Mean acetaminophen concentrations in plasma been suggested that migraine causes a significant
1mg/mI) after a single oral dose to ambulatory (0) and supine
delay in gastric emptying. 21 Thirty minutes after
(•) subjects. The supine position results in delayed gastric
emptying and absorption of acetaminophen. (Data from 900 mg of effervescent aspirin the mean plasma
Nimmo, W.S., and Prescott, L.F.24) salicylate concentration in 35 patients during a mi-
 &trointeStiflal Absorption—Biologic Considerations 31

graine attack was 5 mgi 100 ml, compared with a

value of about 7 mg/ 100 ml in 14 control patients. tfl

0
Impairment of absorption correlated with the se- U

verity of the headache and the gastrointestinal 0.04

,
symptoms at the time of treatment. There is the 1..
=
possibility that severe pain in general may retard 0
4-)
gastric emptying.
I-
The effect of acute migraine attack on the ab-
.0
0.02
sorption of tolfenamic acid, an NSA1D, was stud-
ied in 7 female patients." Migraine attacks delayed 4-,

0
absorption. At 2 hr after oral adniinistratiofl mean I-
rd
drug concentration in plasma s;as about 4 p.g/ml
in the absence of an attack but only 1 .8 .sgfml 0.02 0.04
during an attack meats peak concentrations were gastric eniptyiflcj rate constant
found at 2 hr and 4 hr, rcspecftiely. These findings
are probably the result of the delay in gastric emp-
Fig. 3-6. Relations hi p between the apparent absorption
tying that accompanies a migraine attack. Rectal rate constant 1mm 1 ) and the gastric emptying rate constant
nsetoclopraniide accelerates gastric emptying and (min 1) after a single oral dose of acetaminophen in healthy
absorption of oral tolfenamie acid; the combination subjects-who emptied the drug from their stomachs in a
may be useful for the treatment of migraine in monoexponentiat manner. The line of identity is shown.
Under certain conditions the absorption rate of a drug is
certain patients. rate . Iitnited by gastric emptying. (Data from Clements, JA.,
Not only is gastric emptying an important de-
et 3 1 . 2 9)
terminant of the overall absorption rate. in some
cases it may he rate limiting. In other words, the
gastric emptying. Once the drug reached the small
apparent absorption rate conm of a drug deter-
intestine, absorption was rapid (mean absorption
mined from phannacokinetic s,udies may actually
half-life of about 7 mm).
equal the first-order rate eonflt for gastric emp-
There are many examples of the influence of
tying. This hypothesis was recently tested and con-
drugs that affect gastric emptying on the absorption
finned b y simultaneouSly nieSunng gastric crop- rate of other drugs administered concomitantly
tying and the rate of appearance in blood of
(Fig. 3-7). Propantheline has been found to reduce
acetansioophen after oral administration to healthy
the absorption rate of riboflavin, sulfamethoxazole,
subjects)9 The emptying pat-.ern and the plasma
ethanol, and acetaminophen. mon Intramuscular ad-
acetaminophen concerti ration tme profile were
ministration of meperidine or heroin produces a
closely related. For example. sshen the start of
profound delay in the gastric emptying and ab-
gastric emptying was delayed, there was a corre-
sorption of acetaminophen .34 On the other hand,
sponding lag period during which the plasma con-
metoclopramide increases the absorption rate of
centration did not rise or rose slightly. On the other
ethanol," acetaminophen," tetracycline," and pi-
hand, the most rapid increases in plasma aceta-
vampicitlin)' In most of these cases, there is little
minophen concentrations were found when a sub-
effect on the extent or completeness of absorption.
stantial proportion of the dose emptied in an initial
The motility of the small intestine as indicated
squirt. In those cases where gastric empt)ing could
by small bowel transit time also plays a role in drug
be described as a simple monoexponential process,
absorption. The mean transit time of unabsorbed
there was agreement between she apparent absorp-
food residues or insoluble granules through the
tion rate constant (determined from the blood data)
human small intestine is estimated to be about 4
and the gastric emptying rate constant (Fig. 3-6).
hr.?'
These findings confirin that gastric emptying,
Intestinal transit of pharmaceutical dosage
rather than transmucosal transfer from the lumen forms—solutions, small pellets and several unit
of the stiosli intestine, is the (ate-limiting step in
forms such as nondisintegrating capsules and tab-
the absorption of acetaminophen given orally in
lets—ranged from 3 to 4 hr, independent of the
solution. In all cases, the calculated rate constant
dosage form and whether the subjects were fed or
for iransfer of drug from the small intestine to thC
Iastccl° The gastrointestina l transit (i.e., the time
hloothtrcain was greater than the rate constant for
32 IlPipha rniauu I cs and Clinical Ph a rmacnk Intl cs

other group of pants, the concomitant adminis-

'5
tration of helix. Ir fern ide reduced the steady-state
serum conccntralv.n of digoxin. 42 The effects of
propanthcline and rrcioclopramide on digoxin lev-
Al els in serum are ih result of changes in the extent
Cr of absorption of dioxin.
Drug absorption studies based on recovery of
U 10 unchanged drug in. the urine after a single oral dose
0
z indicate that the h;ias ailahiliny of chlorothiazide is
0
0 only about 20% a:er a 500 rug dose, but increases
z
/8 to 50 17c when the time is. reduced to 50 rug. These
Ui
I nonlinear characiotics suggest the possibility of
0 saturable or Site-' pecitic gastrointestinal absorp-
z I! tion, sensitise to :hanges in gastric emptying and
I' intestinal transit.
iii
0
.i II .'
ll To test this h:.pothesis, the bioavailability of
chlorothiaiide 50) mu was studied in fasted sub-
jects on three dii:renl occasions, the drug given
'I) alone, g iven with propantheline 30 mg, or given
4
-, with metoc!oprar:Je 20 tug. 0 Urinary recovery of
unchanged drugs 23% of the dose when duo-
rothiazide ss as gi'- n alone, increased to 55% whets
TIME, hr
propantheline ;;- o-administcred. and decreased
to 13% w lien gis c -i 's oh metoc loprainidc. The h io-
Fig. 3-7. [he effects of metoclapramiJe (Id and prè-
pentheline (C) on acetamnop h en cor.cerittatiors in plasma availahility of chlroihiazide doubled when stout-
(igmI) after a single oral dose of acetaninnpen. The mid- ach emptyinu rate and intestinal transit were de-
de plot (B) shows the dr..g evel-tirre cjme in control sub- creased by priipar.:heline and was cut in half ss hen
ects. Metoclopramide promotes absorption and propar.the- empt y ing and tra:it were accelerated by metoclo-
line retards absorption by affecting gasrc emptying. (Data
pramide.
from Nimmo, J., et al)-)
Other factors uht influence motility also influ-
ence the bioavaii.bility of certain drugs. For ex-
to reach the cecum after oral administration) of a ample, riboflavin is sell absorbed in children with
constant release-rate tablet was 7.6 hr, on the aver- hypothyroidism but poorly absorbed in children
age, in 4 wbjects. Stomach emptying averaged 3.1 with hyperthyroidism, compared with gastrointes-
hr. Therefore, intestinal transit time was 4.5 hr.39 tinal absorption its healthy children. Treatment of
The rather short residence in the small intestine has the thyroid disorder results in normalization of ri-
implications for the design of prolonged-release boflavin absorption. These findings are consistent
dosage forms. A product designed to release drug with the known effects of thyroid disease on in-
over a 6-hr period may demonstrate poor bio- testinal transit. Accelerated intestinal transit in-
availability if it is rapidly emptied from the stomach duced by a laxtiti' a hisacodyl) markedly decreased
and the drug is poorly absorbed in the large bowel. the azo reduction of suhfasalazine to 5-amino-sal-
Propanthelitse and similar drugs increase small icylic acid 5-ASA) and sulfapyridine in the large
bowel transit time, whereas nnetocloprainide ac- bowcI. 9 Urinar) recovery of 5-ASA after a single
celerates transit through ihe small intestine. The dose was reduced to one-third control levels. Since
extent of absorption of drugs that are incompletely 5-ASA appears to he the active component of sul-
absorbed may be dependent on intestinal motility. fasalazine, the elticacy of sulfasalazine in the treat-
Clinical studies show that propanthelinc increases merit of colitis issax be reduced in patients with
the absorption of riboflavin by more dian twofold pro use ditirnhsea.
in healthy subjects, 30 enhances the absorption of
lsydrochlbrothiazide by about one third 49 and isitro-
PECTS-OFFOOD ON DRUG
furancoin by about 50%,' and markedly increases ORPTION
the steady-state serum concentration of digoxin in - In general, gastrointestinal absorption is favored
patients on maintenance digoxin therapy. 42 In an- by an empty stomach, but the interaction between
 C,i.trotnLesttnaI Absorption—Biologic Considerations 33

food and drugs dunuiai atmeut_ith oral which pass intact from the stomach to the small
medication is almost inevitahl. Furthermore, one intestine and do not release drug until reaching the
should not give all drugs Ott an empty stomach; intestine. Less important effects are observed with
some are irritating and should be administered with well-dispersed dosage forms (e.g., solutions, sus-
or after a meal. pensions, and rapidly disintegrating tablets and
There is considerable evidence that food some- capsules), particularly when the drugs in question
times has a niarkSLd but unprdictabiy effect DO the are water soluble. It follows that the effect of food
rate and extent of drug absorption. Food tends to on drug absorption may depend on the dosage form
decrease the rate of stomach etoptying, due to feed- used. For example, food delays the absorption of
back mechanisms from receptors in the proximal enteric-coated aspirin tablets and digoxin tablets
small intestine, and often dela)s the rate of drug but has no effect on the absorption of enteric-coated
absorption. Food_j ds_o increase gastric pH, aspirin granules and digoxin elixir.
which may in or decrease the dissolution or Recent studies have shown that food has little
chemical degradation of some drugs. Food appears effect on the absorption of cnalapril, 53 an angio-
to interact directly with certain drugs either to en- tensin-converting enzyme (ACE) inhibitor, and
hance or to reduce the extent of absorption. Food isosorbide niononitrate. Enal'april is a prodrug,
stimulates gastrointestinal secretions, which may activated by deesterifleation to enalaprilat, the di-
facilitate the dissolution of poorly water soluble acid form of the drug. The time course of serum
drugs. Food also stimulates hepatic blood flow, concentrations and urinary excretion of enalaprilat
which may have implications for the bioavailability after a single 40-mg oral dose of enalapril is vir-
Of drugs subject to first-pass hepatic metabolism. tually identical whether the drug is given to healthy
The potential for food-drug interactions is suf- subjects after fasting or after a standardized heavy
ficiently great that the US Food and Drug Admin- breakfast. The oral administration of isosorbide
istration now requires studies a to the effects of mononitrate after a light breakfast results in a slight
food on drug absorption as pars of the biophar- delay in achieving peak concentrations in plasma
maceutic characterization of almost every new drug and a slight decrease in those concentrations. con-
intended for oral administration. This requirement sistent with the slowin g of gastric emptying, but
is also being applied to new dosage forms of es- causes no important changes in the area under the
tablished drusts. drug-concentration time curve. Similar findings
Welling, 16 a leading authorits in this particular have been reported for isosorbide dinitrate."
area of drug interactions, has reiewed the litera- The lack of effect of food on the abs'rption of
ture on the effects, of food on dru g absorption. In enalapril is in contrast to the substantial effect of
general, the absorption of drugs taken 30 ruin or food on the absorption of captopril. a related drug.
more before a meal is not affected by food. This Singhvi et al.'' have shown that oral administration
guideline, however, does not appl y to drugs given of I'C1captopril after breakfast decreases the re-
in slowly dissolving or prolonged-release dosage covery of total radioactivity in the urine from 76%
forms. The potential for interaction is greatest (fasted state) to 49% of the administered dose.
when drugs are given with a meal or within 30 ruin Comparing the effect of food on the absorption of
after a meal. Food appears to have little effect on enalapril and captopril. Swanson et al." suggested
drug absorpiion when the drug is given 2 hr or that "oral absorption of enalapril may ... be more
more after a meal. In his reviess. Welling" , places complete than captopril because the sulfhydryl
jnrciiqpS 1itooflç9..prcategOrieS: group of (captopril] hinds to other thiol groups in
interactions resulting in unaffected, delayed, re-, food." The absorption of penicillamine, another
duced, and increased drug absoiplion. sulfhydryl-containing drug, is reduced by about
In most of the cases reported to date, food ap- 50 1/ç when given after a meal compared with the
pears to have either little effect on drug absorption rcults observed in fasting subjects."
or, at worst, it decreases the rate but not the extent s1ost of the penicillins and tetracyclines, certain
of drug absorption. Examples include diguxin, erythroinycin preparations, lincojityci rt, and rifarn-
acetaminophen, pentobarbital sodium, various sul - pin fall into the category of significantly reduced
fonarnides, and cephalcxin.4 absorption after a meal. 067 Absorption of almost
The most dramatic delays is drug absorption all tetracyclines is also markedly reduced when
have been observed with entetic-coated tablets, these drugs are taken with milk or milk products.
34
Biopharflla(CUiICS and Clinical l'Irariira&kitIS

presumably because Of an interaction with calcium '['able 3—I. ttfcO f t)oc on 1hC Abo opt ii if
Riboflavin in FactIr2 and Nonfasting Healthy
resulting in a poorly soluble complex.' ,', The influ-
Subjects'
ence of food on the absorption of antimicrobial
I'rrcvni at,sorbr,I
agents is the subject of a comprehensive review." hose
FasTing Nonrasling
The absorption of other drugs may also he se-
riously impaired when given with food. For ex- 48 (r2
ample, administration of the anticholincrgic drug 10 30 63
propantheline immediately after a meal virtually 5 16 St
abolished its effects on salivation, suggesting a
Data from Lc' Y. 0 nJ ILisko. W.j,
substantial decrease in absorption. In contrast, by-
oscyamine suppressed salivation to the same extent
s;hether given after a meal or to fasted subjects. cosc load %% hen it is taken 30,niin before rather
Another example is hydralazine. Shepherd et than with a meal. -- --
Increased absorption of drugs after a meal is
al." studied the effect of food on hydralazine levels
and hemodynamic response in 6 patients with es- usually rajo nalieed in terms of the following rnech-
sential hypertension. A single oral dose of hydral- anisms: ) delayed gastric emptying causing more
azine (1 ingkg) was given in solution after fasting drug to dissolve before reaching the small intestine
or a longer residence time at ispecific absorption
and after a standardized breakfast.
Hydralazine blood levels were reduced almost sites in the small intestine (' increased gastro-
50% when the drug was gisen after a meal com- intestinal secretions (eg., bile) improving drug soP
pared with the fasting state. The higher blood levels ubil itV (4'direct interaction and soluhilization of
of hydralazine observed in fasted subjects produced drug by food (c 2., high-fat meal s ): food-
a greater change in mean arterial pressure (MAP). related increases in hepatic blood flow causing a
Overall, a statistically significant linear correlation decrease in first-pass metabolism. According to
was observed between the percent decrease in MAP \Vclling," -'the increased absorption of riboflavin
and the log of peak hydralazine concentration in and also chlorothiazide in nonfasting subjects is
blood. The authors concluded that the reduction of probably related to nonsaturation of active absorp-
vasodepressor response when hydralazine is taken tion processes or to slow passage of drug past a
gastrointestinal'absorption window'."
after breakfast suggests that patients with hyper-
The absorption of riboflavin is much greater
tension should take the drug at a fixed time in
when it is taken after a standard breakfast.' The
relation to meals.
Food dramatically affects the absorption of iii- data in Table 3—I suggest tlt the effect of the
meal increases with increasing dose of ii vitamin.
fedipine. 7 ° After a single 10-rug dose, peak con-
centration was136 ngfinl when the subjects were The substantial increase in the bioavailability of
fasted, but only 43 ng/ml after a meal. Time to griseofulvin when g iven with a high-fat meal may
peak concentration shifted from about 1 hr to 3.5 be related to soluhilization of the water-insoluble
drug by lipid components of the meal and by stint-
hr. The mean AUC for nifedipine over the first 6
hr was reduced by nearly 50% when the calcium ulated bile secretions.""
channel blocker was given after breakfast. The high A 20% increase in the urinary excretion of hy-
value observed in fasted subjects was asso- drocliloroth i tizide was found after oral adininistra-
ciated with a large drop in blood pressute and tach- lion of the drug with food compared to that ob-
ycardia. Although the effects of nifedipine were served in fasted subjects. 74 The bioavailability of
less intense when taken with a meal, they remained chlorothiazide is doubled when taken immediately
clinically significant. Taking nifedipine after food following a meal compared to that found in fasting
may reduce vasodilator side effects while retaining subjects." Studies i l l suggest that admin-
therapeutic efficacy. istration of erythromycin cthylsucc mate after a
Tolbutamide taken 30 ruin before a meat lowers meal results in a substantial improvement in bio-
blood glucose in patients with diabetes more ef- availability.tm
fectively than when it is taken with a meal.' 1 This Colburn et al" recently reported that food in-
finding is clinically televani and probably reflects creases the hioavailability of isotretinoin (cis . retj-
both better absorption when taken in the fasted state noic acid), a ret inoid with tow aqueous soluhiht
and higher blood levels of tlbutamide at peak gill- indicated for the treatment of severe recalcitrant
 Gastrointestinal Absorplion — B iologic Considerations 35

Table 3-2. Effect of Food on the lIioavailability of

110' and less than 25% of administered T was
Nitrofurantoin, as Determined from Urinary absorbed after product I. compared with 55 to 60%
Excrction absorption for each drug after product II. Following
Percent excreted administration of I with a high fat meal, the ab-
Fasting Nonlasting sorption of both drugs increased; the percentage of
Dosage form
the dose of ECT and T absorbed front product I
Capsule (macroctystallitse) 22 40
was directly related to the fat content of the meal.
Tablet (microcrystalline) 36 44
Food did not affect the absorption of either drug
-Data from Bales, T.R.. Sequesra, IA. and Tembo, AN." in product Il.
In another study, lithium sulfate was given as a
cystic acne. The standard dosage form of isotre- single dose in slow-release tablets to 30 healthy
tinoin is a soft gelatin capsule containing the drug subjects, fasting and after a standard meal. 8 ' Post-
prandial administration produced practically no ad-
dispersed in lipid; bioavailahility of the drug in
verse effects, whereas lithium on an empty stomach
fasted subjects is 50% or less. Increases in the
caused diarrhea in about 20% of the subjects. Ab-
bioavailability of isotretinoin of 50 to 100% were
sorption was estimated by determining the amount
observed when the retinoid was given with a meal
of lithium excreted in the urine in a group of 10
or I hr after the meal compared with the results
subjects. The drug was well absorbed when given
observed in fasted subjects. The authors suggest
after food, but when given on an empty stomach
the "stimulation of bile flow due to meal antici-
the absorption was lower in most subjects, appar-
pation and ingestion could ha.'e enhanced the sol-
ently owing to more rapid gastrointestinal passage
ubifization [and bioavailability] of isotretinoin."
ii connection with diarrhea. The investigators pro-
Still greater effects of food have been reported
pose, that slow-release lithium preferably be ad-
with etrclinate, another retinoid used in the treat-
ministered after meals.
nient of psonasis. t A high fat meal or two glasses Clinical investigations cons incin'gly demonstrate
of milk increased the peak concentration following
that the bioavailability of certain drugs subject to
a single dose of eretinate 100 lug by more than first-pass hepatic metabolism during absorption is
threefold and the total AUC by 3- to 4-fold. increased after a meal. For example, administration
Administration of nitrofurantoin in commercial of hydralazine following a meal results in a two-
capsules containing macrocrystalline drug or tab- to threefold increase in hioavailability.°
lets containing microcrystalline drug after a stand- Food has also been found to substantially in-
ard breakfast results in more complete absorption crease the serum levels of propranolol and meto-
of the antibacterial agent compared to that obtained prolcil after a single dose:' the propranolol data
after administration to fastin g subjects 9 The effect are described in Figure 3-8. Other studies have
of feed, however, is much more pronounced with shown that the increase in propanolol bioavail-
the macrocrystalline form of the drug (Table 3-2). ability is related to the protein content of the meal.m
In fact, although there are substantial differences The influence of a high-protein meal on the ki-
in bioavailability between the two products in netics of simultaneous iv (unlabeled) and oral (deu-
fasted subjects, no significant differences were ob- terated) doses of propranolol was studied in 6
served when the products were compared in non- healthy subjects.° 5 The clearance of propranolol,
fasted individuals. These findings are important be- as determined fiom the iv dose, was nearly rate-
cause both products are recommended to be taken limited by hcpatic blood flow. The high-protein
with food to improve gastrointestinal tolerance. meal increased systemic clearance from about 1.0
The common practice of using only fasted subjects I
lJmin to 1.4 IJinin; hioavailability (oral AUC X
in bioavailahilit y studies would appear to be in- I00)/iv AUC] increased from 27% (fasting) to
appropriate for drugs that are normally adminis- 45.5% (after meal).
tered with meals. These findings are probably the result of the
Food increases the hioavailability of hydro well-known ellect of tood on splanctsnic blood
chlorothiazicle (HCT) and triamterene (T) from an flow. Meals, particularly meals high in protein con-
incompletely absorbed combination product, but tent, increase splanchnic blood flow transiently but
has no effect on the absorption of these diuretics substantially over fasting values. Olanoff and his
from a well-absorbed product .°' Studies in fasted colleagues, 5t found that hepatic blood flow, esti-
subjects indicated that 30 to 45 1/6 of administered mated by indocyaninc green ([CG) clearance, in'-
36 tti(ph!rlrracetliwc and Clinical t'harmacotsiiiciics

a lbcIcd marker in alcoholic patients and Found to

lI he significantly higher than iii control subjects,
cs en alter up to 4 days of abstinence from alcohol.
In several cases, increased permeability was evi-
dent tip to 2 weeks after cessation of (rinking. lIre
ins c'stigators suggest that increased intestinal per-
5)
0
meability could result in the absorption of toxic,
vi
ordinarily non-absorbable compounds (MW
C
50 <5000), which might accelerate the extraintestinal
C Ii ss tie darn ace common in alcoholics.
C
C
5- Studies concerned with drug absorption i ri pa-
0 tients with malabsorption have been limited, arid
the results of such studies generally have not been
remarkable. For example, the absorption of iso-
riiazid, chioramphenicol, salicylate, and cycloscr-
inc in tO patients with demonstrable villous atro-
phy. 8 of shorn absorbed x) lose to a limited extent,
was similar to that measured in It) healthy control
tire, hours
subjects matched for age and sex investi-
Fig. 3-8. Proprarlolcl concentrations (ng'rnlf in serum ci- sa;ors suggest that the intestinal absorption of
er a sirgie oral dose tO lasted (•) ard fed (C) subjects. dmas by passive diffusion ma y remain largely un-
Oral au.'r.,nstration of propranolot after a meal results in altered in states in which histologic and/or abnor-
higher serum levels. (Data from Metander, A. et al.rO
mal results from nutrient absorption tests indicate
intestinal injury.
creased b y 347c 60 ruSt after the meal, from 1.7 .]though some studies have shown that the oh-
Lniin to 2.3 Umin. In theory, a transient increase sorption of digoxin is reduced nniilahsorptisc
in hepatic blood flow rate during absorption would states.' others hase fouiid\_d ,igoxnibsorption to
allow a larger fraction of the oral dose to evade be normal in such patients."-' Reduced bioavail-
first-pass metabolism and result in an increased ability of digoxin in patients with nialabsorption
bioasailability.16 s ndrome may be the result of delayed or impaired
dissolution rather than a defect in the intrinsic ab-
)AtABSORPTION sorption of the drug. For example, one ease report
/'Malabsorption may be defined as any thsorder showed that a patient wih a radiation-induced mal-
with impaired absorption of fat, carbohydrate, pro- absorption syndrome absorbed digoxin poorly from
tein, vitamins, electrolytes, minerals, or water. a tablet preparation but that substitution of digonsin
Drtie-induced, malabsorption has been observed elixir overcame the bioavailability prob!ern3
after administration of neonsycin, phenytoin, ami- Other investigators 94 have shown that high-dose
nosalicylate, and certain antineoplastic agents such chemotherapy [carmustine (BCN U) or cyclophos-
as methotrexate. 11 5-Fluorouracil (5-FU) damages pharnidel and radiation therapy decreased the ab-
the gastrointestinal epithelium and impairs the sorption of di-oxin by about 50%, when the drug
function of the mucosa to serve as a barrier to large was given in the form of a tablet. A much smaller
polar molecules. The absorption of polyvinylpy- effect, a reduction of only 15%, was noted sshen
rolidonc (PVP) and tobramycin, both of which are the drug was given as a solution inside a capsule.
ordinarily rather poorly absorbed, is substantially Chemotherapy- and radiation-induced malabsorp-
enhanced in patients receiving a course of 5-FU tion of digoxin can he influenced by the pharma-
therapy. 98 Patients with intestinal malabsorption in- ceutical formulation.
variably lose wcight/)Ihe most important clinical ftc difficulty of maintaining a therapeutic phen-
phenomena are uswflly those of lipid deprivation, ytoin concentration in a patient who developed sei-
including signs of fat-soluble vitamin (i.e., vita- zures while undergoing treatment for a malignant
mins A, D, E. and K) deficiencies. tumor with cisplatinum, vinblastine, and bleomy-
Chronic alcoholism may also lead to a leaky cin was documented by Sylvester et al. Low se-
gut.,,, Intestinal penacability was investigated with rum levels and poor control were observed during
 C.astrointcstinat Absorption-Biologic Considerations 37

chemotherapy despite relatively high oral doses of pass receiving phenytoin are likely to require much

phenytoin. The investigators related these findings higher oral doses to achieve adequate blood levels
to changes in the intestinal niucosa induced by the of the drug because absorption is only about 30%
cytotoxic drugs, resulting in impaired absorption of normal. In some cases, bioavailability in in-

of phenytoin. Based on serum levels and urinary testinal bypass patients may be improved by giving

excretion data, the authors calculated that the pa- a more rapidly absorbed form of the drug.

tient absorbed only about 20% of the administered

REFERENCES
dose of phenytoin; bioavailahility of phenytoin in
1. Fordiran, J.S., ci at.: Permeabilit y characteristics of she
healthy volunteers is greater than 80%. human small intestine. J. Clin. Invest., 44:1935, 1965.
An investigation of propranolol found that hio- 2 Schedt. H.P.: Absorption of steroid hormones from the
availability on oral administration was similar in human small intestine. J. Clin. Endocrinot, Metab.,
25:1309, L965.
normal subjects and patients with untreated celiac
3. Wass, M., and Everd, D.F.: Transport of pCnicilamine
disease."' Direct perfusion of the proximal jeju- across rioieosaof the rat small intestine in vitro. lliochem.
num, however, indicated that propranolol absorp- E'harraaeol., 19:1287, 1970.
4. Fvered. D.F., and Randall, HG.: Absorption of amino
tion is reduced about 70% in celiac patients com-
acid derivatives of nitrogen mustard from rat intestine in
pared to normal subjects. The results suggest that, vitro. Biochem. Pharmacot.. 11:372, 1962.
ordinarily, propranolol is absorbed in the duode- 5. Schanker. L.S., and Jeffrey. ii: Active transport of for-
eign pytimidines across the intestinal epithelium. Nature.
num morphologic changes 'in the intestine distal
190:727, 1961.
to the optimum absorption site have no effect on 6. Schanker, L.S.. and Tocco, Dl.: Active transport of some
pyrimidines across the rat intestinatepiihettum. J. Pha.r-
propranolol bioavailability. On the other hand, the
macnt. Exp. Ther., 128:1 15, 19.
absorption of propranolol from prolonged-release 7. Levy. G.. and Jusko, WI.: Factors affecting the absorption
products may be impaired in patients with active of riboftavin in man. I. I'harm. Sci.. 55.285, 1966.
8. 'thomson, A.U. and Lee. CM.: Observations on the
celiac disease.
mechanism of thiamine h)dnochlortde absorption in man.
Concern that senini levels of cyclosporine may CIrn. Sc., 43:153, 1972.
he inadequate in some patients prompted Atkinson 9. Mayeruohn, 1st.: Ascorbic acid absorpiloti in nian.ph:ic.
niacs,lstnetie implications. hut J. Pharriiacot.. 19:140.
et al.° to determine cyclosporine concentrations
1972.
during oral and iv therapy in 56 patients receiving tO. Crouthamel. W.G.. ci at.: Brad absorption. IV. Influence
of hema- of absorption kinetics of seakt acidic drigs. J Pharm
hone marrow transplants for treatttserl
Sri,. 601160. 1971
tologic malignancy or severe aplasttc anemia. Pa-
ii. Cooke. A.R.. and Hunt,l.1s.: Absorption of acetylsztttcvlic
tients with no clinical intestinal dysfunction (no acid from unbuffered and buffered gasinc contents. Am.
vomiting or diarrhea) consistently demonstrated J Dig. Dis.. 15.95. 1970.
12. Cooke. A.R and tlirchall. A.: Absorption of eihanoi from
high serum levels after an oral dose. In contrast, the stomach. Gastroenierotog. 57:269. 1969.
patients with intestinal disease (e.g.. cherrioradia- 13. Granrer. B.. and Baker, K F.: Electron microscope in-
vestigation of the striated border of ie:es:iii.sl epithelium.
lion enteritis, graft-versus-host disease of the in-
Anal. Rec., 107:423, 1950.
testine. or Candido enteritis) showed poor absorp- 14. Wilson, I P.: Surface area of the small inie,nne Sri roan.
tion of oral cyetosporine. Intestinal disease had no Gut, 8:618, 1967.
IS. Chadwick. V.S.,Philtips, S.F.. and Iiofnianti. A t: Meas-
effect on serum levels of cyclosporine after iv in-
urement of intestinal permeability using loss molecular
fusions. The authors concluded that the iv infusion weight polyethylene glycols PEG 4130j. ll..Application to
normal and abnormal penneab:Itts states in roan and au
of cyclosporine is reliable and is the indicated route
orals. Gastroenterology. 73:247. 1977
when tnalabsorption or intolerance of the oral prep- ifs. Booth. CC.: Sites of absorption in the small tnte'tine.
aration occurs. Fed Proc.. 76:1563, 1967.
7, Winne. I).: influence of blood 8ou on intestinal absorption
Surgical resection of the small bowel can result
of xcnobitics. Pharmacology .2/:t. 1950.
in impaired absorption of digoxin as is cli as other IS. ttarwiie, A., Robinson. KG.. and Herrin, WE.: Prolon-
drugs. Reduced bioavaitahility of digoxin was gation of gastric emptying b' oral propaniheline. ('tin.
Ph.imsacol Ther., 22.206. 1977
found in 5 of 9 patients who had undergone jcjunal
19 Horton, RE., Ross. F.G.M.. and Darting. Gil.: Deter
h\ trss surgery.'° A strong correlation was nutd itunasiOn of the emptying time of the stoniach by use 01
between the length of jejunum remaining in con- cnieric.coated barium granules. Br. %1d. I.. 1:1537. 1965
20. itl y slie, RH., Grass, G.M.. and MacBennett. 1).R.: For-
tinuity and the area under the digoxin concentration ttrulation and evaluation of entenecouted aspirin iahleis.
its Serum versus time curve. The bioavailability of Am J. Pliarin.. 131:206, 1959
liydrsichlorotlu:ir.ide is reduced by 50e in patients 21. Wagner, 1G.. Vetdkamp. \V and Long, S : Enteric coat
ings IV. irs viso testing of granules and ijirleis coated with
whit had undergone intestinal shunt operations for styreric-itisteic acid copolymer. I Phiarm. Sci., 49:128.
obesity." Epileptic patients with an ileojejunal by- 1960.
 lfitrptlarmce'utic.S aml Clinical lliarmacol'inrlica
38

22. I Ictiding. R C c al : 'lire dcperrikrrce of parac eta in , l .ib' 46. Welling, P 6.: lnrrrartiiirms affectin g drug ;ihsnrptmsmn. (liii.
Pharurmacokun , 941)4, 1984.
silrpt ii iii illS the rate of gastric emptying. Br. 3. l'hartiiavol
47:415, 1973. 41. White, R 3.. ct uI.: 1lasnma cutsccntr:itiont of digoxin alter
23 Logan, E.P.A cia1.: Effect oIcimctrdifleOn scnttfl gaston oral administration it the lasting and posiprandial state.
and gastric emptying in man. Digestion, 18:220, 1 978. Br. Med. 3., 1:31501, 1971.
48 lalle, J.M.. Cola/ii. J.L , and Barry. Ii.. I:lf.s of ilL
24. Nitntiio, W S and Prescott, LF.: The influence of posture crony components rut gastrointestinal absorption of r,vcta-
on pa-racetamol absorption. Br. J. Cltn l'luarmacol 5:318,
niinophen tablets in tnan. J. Plmarm. Sri.. 60.1646, 1971.
1978 49 Smith. R13.. ctal.: IharinarsikirteticS of penlobarbital after
25. Encnaucr, R.\V . Bass, J.W., and McDonnell. IT.: intravenou.s and oral administration, J. Pharmacokinet.
Esphagcal ulceration associated nib oral thcophy line.
N. Engl. J. Med., 310:261, 1984. Biopharm.. 1.5, 1 973.
50. \lac[)onai'd. It.. ci al: Effect of food on absorption of
26. Channcr, K S., and Roberts, C.J.C.. Effect of dela)ed
csi>jittagcal transit on acetaminophen absorption. Clin. sulfonanti 2cs its nan. Chcmtiiitftcrapy. 12:292. 1 967.
SI. liarvengt. C ct al. Cephradine absorption and excretion
l'hartiiacol. 'I her.. 37:72, 1985.
in fasting and nosfastin g volunteers. J. Clin. Pharmacol..
27. Volans, (iN.: Absorption of effervescent aspirin during
migraine. lIe. Med. J_ 4:265. 1974. 13:36. 193.
52 Welling. P (3.. Itifluence of food and diet on gastrointestinal
28. Tokola. R.A.. and Neuvoncn, P .1.: Effects of migraine drug abscc'ption: a review. J. Phmamtacokinet. Biopharm..
attack and nretoclirpraniidc on the absorption of tolfenamic
acid. lIr. J. Curt. Pharmacol., 17:67, 1 984. 5:291, 197.
29. Clements. I A., ci al.: Kinetics of acetaminophen absorp- 53. Swanson. RN.. and VLusscss. P II.: Influence of food on
tion and gastric cmpr)ing in man. Clin. Pharnntacol. Ther., the bioasar!ability of enalapril. J. Pliarm. Sci., 73:1655,
1984.
24420. 1978.
54. Laufen. H . and I.eitold, 51.: The effect of food on the
30. Levy, (3., Gibaldi. 51 . and Procknal, J.A.: Effect of an oral ahsoriron of isoxorbide'5-nutouoflttrate. Br. J. Clnns.
atiticholinergic agent on riboflavin absorption in man. I.
Pharmaco!.. 18:967, 1984
Phaiitt. Sri . 61:798, 1972.
55. Taylor. 1.. et al.: Isosorbimle diusitrate phnrmacokrnreticu.
31. Antonioli. EA , ci al.: Effect of gastrectonty and of an Arutieim. Fuusrh .32: 1 'Q- 9 , 1982.
ntrcholinergic drug on the gastrointestinal absorption of
56. Singhvi. S M., et al.: Effect of food on the bioavarlabtlity
culfon;urriide in man. 1st. J. Chin. Phurrnacol .5:212, 1971. of captopnl is healthy subjects. J. Cliii. Pltarnsaeol.
32. (",1r'cons. 1)0.. and Last, A.F.: Effects of intravenous and 22:135, 1;81.
'st.'l pripanthchine and metocloprainide on ethanol imbsitrp'
57. f)sntau. NI .A., ci al : uvduttion in umuiil pemctllamirie ab-
t.mClis. Pltarmacol. The r., /7:578, 1975. sorption hr food, antacid, and ferrous tulfa'ie. Clun. l'hax-
33 Ninritro. I . et al: Pharmacological mirdiftcatton of gastric macuI. Thrr. 33465, 1989,
.:iOptyiflg. Effects of prirpantheline and tnetoclopraitiide on 59. Kirby, W.\l iii,. Roberts. C I-.., and Bardick. RE.: Coin-
paracetarnol absorption. Br. Med. J.. /587. 1973. parson o f 'so sex tetracclines with trtracnclune and dc
.i-1 . Nimmno, W,S., ci al.: Inhibition of gastric emptying and methl lchIc'rtctraccline. Aniimicrob. Agents Chetnoiher..
drug absorption by narcotic analgesics. Br. J. Clin. Phar- 1961.p. 21/6,
marol., 2509, 1975. 59. Klein. JO., and Finland. 51 L : The new penicitlinr. N
35 Nimiuro, J.: The influence ofuutetocloprarnide on drug tb Engl. J. Sled., 269:1019, 1963.
si..rption. Postgrad. Med. J.. 49(Suppl.):25, 28. 1973. 60. Welling, PG.. Ct all.: Bioavamlabnhity of amptcihlin and
36. Gorhoni, Co., et al.: Absorption of antibiotics: lnfluc'ncc of antoxiciltin in fasted and notifasted subjects. J. Pharttr.
rnctocloprarnide and atropine on serum levels of p/sam. Sci., 66.549. 1977.
picillin and tetracycline. Ann. Clin. Rca., 4:228, 1972. 61. Kaplan. K., Chew, \V.H., and Weinstein, L,: Microbio-
37. Eve, I .S.: A review of the physiology of the gastrointestinal logical, pharmacological and cI inical studies of lincontycin.
tract in relation 10 radiation doses of radioactive materials. Ant. 3, Sled. Sci., 250:137, 1965.
Health Phys., 12:131, 1966. 62. Siegler, 0 I , ci at.: Effect of steals on nifampicin absorp-
38. Davis, S.S., Hardy, 3G., and Fara. J.\V.: Transit of phar- tion, Lancer, 2:197. 1974.
maceutical dosage forms through the small intestine. Gut. 63. Welling. PG.. ci al.: Bioavailabiliiy of tetracycline and
27:886, 1986.. donycycline in fasted and nonfasied subjects. Antimicrob.
39. Wilson, C.G., and Hardy, 3G.: Gastrointestinal transit of Agents Chentother.. 11:462. 1977.
an osmotic tablet drug delivery system. 3. Pharm. I'har- 64. Welling, PG., Ct al.: Bioavailability of erythromycin stea-
tttacol., 37:573. 1985. rate: Influence of food and fluid volume. J. Pharrn. Sen.,
40. llccntranrt. B., and Groschinsky-Grtnd. 51.: Enhancement 67:764, 1978,
of the gastrointestinal absorption of hydrochlorothiauidc by 65. Rutland. J., Berend, N., and Marlin, G.E.: The influence
propatitheline. Er.m. J. Cliii. Pharmacol., 13:385, 1978. of food on the bioavarl:ubility of new formulations of eryth-
41. Jaffe, 3M.: Effect of propantheline on nitrofurantoiti ab. runsycin srearatc and base. Br, J. Clin. Phartnacok.8:343,
sorption. I. l'hams. SeE, 64:1729, 1975. 1979.
42. Mannitten, V., et at.: Altered absorption of digoxin in pa- 66. Rosenblatt. i.E., et at.: Comparison of/n vitro activity and
clinical phartivacology of donycycline and other tetracy-
tients given propantheline and i netoclopratiside. Lancet,
clines. Antiutsictob. Agents Chentothe. 1966, p 134.
1:398, 1973-
67, Welling, PG.: The influence of food on the absorption of
43. Osman, NI., and Welling, P.O.: Influence of propantheline antimicrobial agents. J. Anlimicrr'ub. Chemother., 9.7,
and nrctc'clopranide oil the bioavailahiltty of cltlorothia-
ziuie. Cure. Then. Res., 34:404, 1983. 1982.
44 Levy, G., MacGillivray, M.H., and Procknal, l.A.: Ri- 68. Ekcnved, G., ri al.: Influence of food on the effect of
prcmpantheline and I.hyoncyarnsitie on salivation. Scand. J.
boflavin absorption in children with thyroid disorders. Pe-
diatrics, 50.896. 1972, Gastroentetul.. 12:963, 1977.
45 VanHees, PAM.. CI xl.: Influence of intestittal transit tithe 69. Shepard. A.M.M.. Ii-vine, NA.. and Ludden.T.M.: Effect
of food on hli'u..nd hadralacine levels. Cl/n. Phartiutcol,
on azo-reduction irfsalicyarosulphaplridine. Gut, 20:309.
1979. Then, 36:14. 1984.
 39
(;astri,inteslinal Absorption- Biologic Consicknauions

85 Olanmuff. 1.. S.. ci at.: Food effects on propranotot systemic

70. Ilirasawa. K., ct al,: Effect of food ingestion on riifcdtpine arid oral clearance: suippuirt for a blood flow hypothesis
absorption and haemodynatTtiC re)nse Fur. 3. (tin PluU- Clin. t'lr.irriu.ici,I. 'flier., 40.108. 19116.
macut , 28:105. 1995. 86. McLean. A 3.. ci at.: Food. splanchntC blood flow, arid
Samaria, A. • Ct at. Improved effect of tulbntariiide when hioas ,itlahuluty (if drugs subject to first . pass metabolism.
11ivcrs before food in patients on long-term therapy. Br. J. ('tin. Pharriracul. [her.. 24 5. 1978.
Cliii. 1hartnacol., 18.647. 1981. t11 R.rhtivaii. F.. and Cain, 0.1).: Current concepts in therapy:
72. Croarise, R.G.: human phamiacotuigY of grtscotulS in he Drug-induced malahsuutptton-A review. South. Med, I
effect of fat intake on gastrointestinal absorptiui:i. 3. trusest.
66:724. 1973.
Dermatol.. 37529, 1961 88 Sthcr, OR.. Mayer. Ri.. and Lc'in, M 3.: Increased gas'
Kabatakalaun, P., ci at.: Parameters affecting absorption rroinre xt irat :ihsisrpt ion of large molecules in patients after
of griseuufulvunin a human subject using urinary nictatailute 5.fluoruiuracil therapy for metastatic colon carcinoma. Can-
excretion data. J. Pharm. Sc., 59:595, 1970. cer Res.. 40.3430. 1980.
Beermaxn, B., and Groschinsky . Grind. 81.: Gastrointes- 81 llj;urnason. I., Ward, K . and Peters. ....J.: The leaky gut
tinal absorption of hydrochlorothiaiide enhanced by con- of alcunbolistii: possible route of entry for toxic conipotinds.
conritafli intake of food. Fur. J. Clin. Phamiacal.. 13:125, Laticet. 1.179. 1984.
19711. 90. Mattiha. 1.).. Jussila. I.. and Talcki, S.: Drug absorption
75. Welling. P.O., and Barbhaiya. R 11.: Influence of food and in patients s; itt intestinal vilhcuus atrophy. ..rerteimitrCl-
lard volume on chlorothiazide biuuavailabulily: comparison forsch.. 23:5113. 1973.
of plasma and urinary excretion mCLhOdS. J. Pharru. Sri..
91. Halt. \V.l1., and Doherty. I.E.: Tritiated diguixin. XXII.
7132. 1982. Absorption and excretion in malabsorption syndromes.
niycifl cthil-
76 Cone, T.C.. et iii .: BioasailabililY of erythrO Ann. I. Mcd.. 5u1:437, 1974.
succinate in pediatric patients. J. Cliii. Pharniacol., 18.194, 92 Gerson. CD.. Lowe, El]., and Lindcnhaum. .1.: Bto-
19-18. availability of digosin tablets in patients si tth gasirointes'
- Ccbunn. \V.A.. Ct at.: Food increases the biruasaulabituty unat du slunction. Ann. ).Med., 69:43. 1980.
of jsotrctinoin. J. Cliii. Phamracol.. 23:534. 1983. 93 Jusko. \V 3.. ci at.: Di xin absorption from tabletsgoand
Coburn, WA., ci at.: Effect of meals on ihe kinetics of elixir. The effect of radiation . induced malabsorption.
etierinate. 3. Clin. Pham-uaeol.. 25583. 1985. jas1 'lO't554. 1974.
79 Bates, T.R., Sequeina. IA.. and Teotbo. AN.: Effect of 94. I3jornssOn. TI) e t at.: Effects of high-dose cancer che-
food on nitrofurantoirt absorption. Clin. Phaumacuut. Ther.. iiothcrapy on the absorption of digoxtn in two different
1663, 1974. formulations. Cliii. Pharroacol. Ther., 39:25, 1986.
SC1. Williams: R.L., et at.: Effects of formulation and food on 95. Sylvester. R.K.. ci al.: impaired phenytoin buoavatlability.
the absorption of hydrochiorOthiazide and uiamteiene or secondary to cis-platinum. sinhlastine, and bleoinycin.
armioride from combination diuretic products. Phanur. Pier. [)rug Monitor. 6:302. 984.
Res , 3:348, 1987. 96 Sandle. 01.. ci al.: Propraxolol absorption in untreated
I Jeppson. 3.. and Sjogreri. .1.: The influence or food on side coeliac disease. Ctin. Set.. 63.81, 1982.
effmis and absorption of lithium. Aria Psychiatr. Scant.
97. Atkinson. K.. ci al.: Detrimental effect of intestinal disease
51258, 1975. on absorption of orally administered cyclospone. n Trans-
2 blelander, A., ci at : Enhancement of hyilralaZine bio-
plant Proc.. 15:2446. 1983.
as ailability by food. Cho. Pharrnacot. Ther,.22: 04. 1977. Backman. L.. ci at.: Malabsorption of hydrochlorothiaiide
8 3. Silelander, A., ci at : Enhancement of the bioavailabtlity following intestinal shunt surgery. Clin. Pharniacokituci.,
of proprunotol and metoprolol by food. Clin. Pharroacol.
4:63, 1979.
Ther., 22:108, 1977.
99. Kennedy. 81.C.V.. and Wade, D.N.: Phenytoin absorption
4. 'AnIle. 1., et a].: Food-induced increase in proprat7olol in patients with ileojejunal bypass. Br.). Chn. Pharmacol.,
bioavatlabilitY_-Relationship to protein and effects on me-
7:515, 1979.
tabolites. Cliii. Phamiacol. Ther.. 30:790, 1981.