Symposium on Individualization of Drug Therapy

Gastrointestinal Absorption of Drugs

Drugs

L. F. Prescott, M.A., MD.,

M.D., [Link].E.*
F.R.C.P.E.*

INTRODUCTION

Although the commonest and most convenient method of drug ad-

ministration is by the oral route, absorption from the gastrointestinal
tract is a complex process which is subject to many variables. Physiolo-
gical factors and disease states are known to have important effects on
drug absorption in experimental animals, but little is known of their sig-
man. There is often marked individual variation in the rate of
nificance in :man.
drug absorption, and slow or incomplete absorption is probably a common
but rarely recognized cause of therapeutic failure in clinical practice.

MECHANISMS OF DRUG ABSORPTION

Most drugs are thought to be absorbed from the gastrointestinal tract

by passive nonionic diffusion or by active transport. Other mechanisms
such as facilitated transport, passage through membrane pores, and
pinocytosis seem to play only a minor role. 33 Passive diffusion is the most
important mechanism and depends essentially on the movement of drug
across the mucosa to the circulation down a concentration gradient. The
rate of transfer depends on the concentration gradient, molecular weight
and size, lipid solubility, and mucosal blood flow, surface area, and per-
meability. The epithelial cells function as a lipid membrane which is per-
meable to lipid-soluble compounds but relatively impermeable to highly
ionized water-soluble substances. According to the pH-partition hypoth-
esis, weakly acidic drugs are largely un-ionized and lipid soluble in acid
solution and should therefore be absorbed best from the stomach. The
converse applies to weakly basic drugs which are absorbed primarily
from the more alkaline contents of the small intestine. 55 The absorption of
strong organic acids and bases such as phenol red, guanethidine, and
quaternary ammonium compounds is generally poor and variable, since
ionization is virtually complete over the whole physiological range of pH.

*Consultant Physician. The Royal Infirmary,

':'Consultant Physician, Infirmary. Edinburgh,
Edinburgh. and Senior Lecturer in Clinical Phar-
macology, University Department of Therapeutics, Edinburgh, Scotland

Medical Clinics of North America- Vo!.

Vol. 58, No. 5, September 1974 907
908 L. [Link]

Although pH-dependent absorption from the buccal mucosa, stomach,

and intestine can be readily demonstrated in model experiments, in prac-
tice the stomach does not seem to be an important site of drug absorption,
and many observations are contrary to the traditional pH-partition theory.
Furthermore, the commonly held belief of pharmacologists that the pH
of the resting gastric contents in man is always in the range pH 1 to 2 is
quite erroneous. Values exceeding pH 7.0 may be encountered routinely
in individuals without gastrointestinal disease,35 and achlorhydria is com-
mon in the elderly.
Ethanol and many weakly acidic drugs are absorbed much more
slowly from the stomach than from the small intestine. 20 20 For example,

warfarin is absorbed more rapidly from the duodenum in man even at pH

8.0 than from the stomach24 24 and more than twice as much phenobarbital,

pentobarbital, and ethanol are absorbed from the small intestine in ten
minutes than from the stomach in one hour. The much faster absorption
of drugs from the upper small intestine is thought to be due to the very
large surface area at this site. The rate of gastric emptying therefore
markedly influences the rate at which drugs are absorbed, regardless of
whether they are weak acids, weak bases, or neutral compounds. 27 27

Inorganic ions, sugars, amino acids, vitamins, and purine and pyrimi-
dine bases may be absorbed from the small intestine by active transport
systems. Drugs such as L-dopa and 5-fluorouracil which are related to
these naturally occurring substrates are thought to be absorbed by the
same mechanisms, and it is possible that some compounds are absorbed
by both passive diffusion and active transport. Drugs do not seem to be
absorbed via the small intestinallymphatics to any significant extent. 1010

Dissolution
Before a drug can be absorbed it must dissolve in the gastrointestinal
fluids, and dissolution can be a rate-limiting step in the process of absorp-
tion. Many drugs are relatively insoluble in aqueous solution, and solubil-
ity is often highly dependent on the pH. Acidic drugs are more soluble in
alkaline solution, whereas the solubility of bases is greater in acid solu-
tion. Similarly, the rate of dissolution and absorption of sodium salts of
acidic drugs (e.g., barbiturates) is usually greater than that of the parent
acids. Although the same effect may be observed with basic drugs and
their salts (e.g., quinine and quinine sulfate), dissolution is generally
rapid in acid gastric contents. Changes in the pH of gastrointestinal
fluids can have opposite effects on the rate of drug absorption. Aspirin,
for example, should be better absorbed from solutions of low pH, since
more drug is then present in the lipid-soluble un-ionized state. However,
aspirin is relatively insoluble under these conditions, and in practice the
drug is absorbed more rapidly from buffered neutral or alkaline solutions.
In addition, the stomach empties more rapidly when the contents are
neutral or alkaline,6 and pH may influence the rate of softening and
disruption of gelatin capsules. The dissolution of drugs may also be
modified by the formation of more soluble complexes and the presence of
bile salts and other surface active agents. 15
15
GASTROINTESTINAL ABSORPTION OF DRUGS 909
Gastric Emptying and Gastrointestinal Motility
Since drugs are poorly absorbed from the stomach, the rate at which
it empties determines the rate at which drugs are delivered to the sites of
maximal absorption in the small intestine. Gastric emptying may there-
fore limit the rate of absorption unless this is normally very slow. The
clinical significance of delayed or slow absorption obviously depends on
the circumstances. It may be important if rapid onset of action is required
or if elimination is so rapid that effective plasma concentrations cannot
be achieved. On the other hand, slow absorption of very long acting drugs
such as warfarin would be of little consequence, although a change in the
total amount absorbed could be disastrous.
The rate of gastric emptying depends on factors such as autonomic
and hormonal activity and the volume, composition, viscosity, tonicity,
pH, and temperature of the stomach contents. 27 27 It is also influenced by

many commonly used drugs, bile salts, and surface active agents such as
dioctyl sodium sulfosuccinate. 15 15
Delayed gastric emptying may also inter-
fere with absorption through another mechanism. Drugs such as
L-dopa, methyldigoxin, and ana. penicillin are metabolized or degraded in
the stomach, and if emptying is delayed the amount available for ab-
sorption is reduced.
The absorption of poorly soluble drugs or compounds absorbed by ac-
tive transport from a limited area of the small intestine may depend on
the rate of gastrointestinal transit. If it is rapid, there may be insufficient
time for complete dissolution and absorption. This effect has been de-
scribed with riboflavin and some preparations of digoxin. 28 31
28 •,31 On the
other hand increased peristalsis may in some circumstances enhance
absorption by causing more rapid tablet or capsule disintegration and
dissolution. Drugs such as cardiac glycosides, isoprenaline, chlorproma-
zine, salicylamide, and L-dopa are metabolized by the gastrointestinal
mucosa, and salicylazosulfapyridine undergoes azo-reduction and cleav-
age by lower intestinal bacteria prior to absorption. Changes in the rate of
gastrointestinal transit could modify gut metabolism with corresponding
changes in the amount of intact drug available for absorption.
There may be further substantial drug loss by metabolism during the
first passage through the liver to the systemic circulation (the "first pass
effect"). The amount of drug lost depends on the rate of absorption, the
hepatic extraction ratio, and the portal blood flow. This probably explains
why so many drugs are less effective when given orally than parenterally.
The maximum plasma concentrations of lignocaine following an oral
dose of 400 mg are lower than those achieved with half the dose given in-
tramuscularly, and chlorpromazine concentrations after oral administra-
tion are only about a third of those obtained with the same intramuscular
dose. 22
22 Similarly, propranolol is taken up avidly by the liver after the first

oral dose, and the amount of unchanged drug reaching the systemic
circulation is not directly related to the dose absorbed. 12 12 The portal blood

flow is not normally considered to influence the rate of drug absorption in

man, but can limit digoxin absorption in animals. 18 18
910 [Link]

Table 1. The Effect of Food on Gastric Emptying and the Hypnotic

Action':' of Phenobarbital in Rats':~':~
Action':~ Rats':'"
% OF DOSE RE-
MAINING IN
ONSET OF DURATION OF STOMACH AT
DOSE (MG/KG) ACTION (MIN) ACTION (MIN) 30 MIN

Fasting 100 28 ± 7.2 227 ± 24 7.7

Nonfasting 100 No effect No effect 40.5

"Loss
':<Loss of righting reflex in groups of 10 and 11 rats.
':<>:<From Kojima, S., et al.: J. Pharm. Sci., 60:1639,1971.
"*From 60:1639, 1971.

Permeability
During the process of absorption, drugs must cross several cell
membranes before reaching the portal circulation, and the rate of
transfer depends on the membrane permeability. Permeability can be al-
tered by many substances, including bile salts, surface-active agents, and
sugars and by changes in the concentrations of inorganic ions such as K+
15 . 33 Ethylenediaminetetraacetic acid increases the rate of ab-
Ca++!5,33
and Ca++.
sorption of several drugs, but mechanisms other than removal of calcium
may be involved. 13 Drugs themselves may alter membrane permeability.
Thus intestinal transport of L-dopa is diminished by chronic treatment
with chlorpromazine and phenobarbital,41 whereas the permeability of
cell membranes to some drugs is enhanced by insulin and many polypep-
tides. 88 The clinical importance of such effects is unknown.
Food
Drugs are usually absorbed more slowly when taken with food, and
the total amount absorbed is often decreased somewhat. 17 ., 34.34, 45 This effect

is attributed to the delaying effect of food on gastric emptying, dilution,

and possibly adsorption of drug onto food constituents. 27 In many cases,
constituents,27
however, food can seriously interfere with absorption. For example, the
area under the plasma concentration-time curve of pivampicillin is al-
most halved when the drug is taken with food,14 and the absorption of te-
tracycline taken with a typical breakfast is negligible. 25 25 Food may delay

gastric emptying and slow down the absorption of phenobarbital to such

an extent that the hypnotic action is abolished (Table 1). In contrast, the
absorption of riboflavin is enhanced by food, and griseofulvin absorption
is greatly increased by a fatty meal. 77 Prolonged fasting reduces the rate of
rats,t1 but it is not known whether the same effect
drug absorption in rats,ll
occurs in man. Food can obviously have profound effects on drug absorp-
tion, yet doctors rarely give their patients precise instructions on this sub-
ject.

Individual Variation
Considering the number of factors which can modify drug absorp-
tion, it is hardly surprising to find enormous interindividual differences
in the rate of absorption of many drugs even under well controlled condi-
GASTROINTESTINAL ABSORPTION OF DRUGS 911
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PATIENTS

1. Individual plasma paracetamol concentrations in 43 fasting patients one hour

Figure 1.
after an oral dose of 1.5 gm.

tions in healthy volunteers. The literature is replete with examples, but

few investigators draw attention to this variation, and it is usually
disguised by presenting data as mean values. An example of the state of
affairs encountered in practice is shown in Figure 1. Forty-three fasting
hospital patients were given 1.5 gm of paracetamol (acetaminophen)
orally, and one hour later there was roughly an BD-fold range in the
plasma concentrations. Similarly, we have shown striking individual
variation in the absorption of tetracycline and phenacetin in fasting
healthy volunteers. 39 Many other examples could be cited. In the case of
paracetamol, individual differenceS
differences in the rate of absorption are probably
due largely to variation in the rate of gastric emptying,20
emptying,2o and this probably
also applies to many other drugs. Paracetamol absorption is delayed dur-
ing sleep,34 and drugs may be absorbed very poorly by neonates.
Effects of Disease
Surprisingly little information is available cocerning the effects of
gastrointestinal disease and other pathology on drug absorption. We have
observed grossly impaired absorption of paracetamol in patients with
delayed gastric emptying and pyloric stenosis, and therapeutic failure of
orally administered drugs seems inevitable in patients with gastric
stasis. 20
20 ,, 37 L-Dopa may be ineffective in patients with slow gastric empty-

ing.2
ing. 2
Conflicting results have been obtained in drug absorption studies in
patients with achlorhydria. 19. 19 , 44 According to the pH-partition hypothesis,
912 L. F. PRESCOTT
[Link]

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HOURS AFTER INGESTION

Figure 2. Mean plasma salicylate concentrations in achlorhydric and control patients

following an oral dose of 900 mg of acetylsalicylic acid. (From data of Pottage et al.: J. Pharm.
Pharmacol., 26:144,1974.)

the absorption of aspirin should be slower in achlorhydric patients, but

effect.3s
we have observed the completely opposite effect. 38
Aspirin was absorbed
significantly faster and plasma salicylate concentrations were higher in
achlorhydrics than in controls (Fig. 2), and this could not be attributed to
more rapid gastric emptying, since paracetamol absorption was identical
in both groups of patients. The aspirin may have dissolved more readily in
the gastric contents of achlorhydrics.
Abnormalities of drug absorption have been observed in postgastrec-
tomy patients and are probably related to changes in gastric emptying
and gastrointestinal motility. However, in one study there was complete
failure of ethionamide absorption in some patients which was attributed
to poor drug solubility and rapid gastrointestinal transit. 32 32 The absorption

of isoniazid, sulfafurazole, and slow release aspirin is decreased when di-

arrhea is induced by lactose in patients with lactose intolerance, and sim-
ilar effects were produced by saline catharsis in healthy controls. In an-
other study the absorption of ampicillin and nalidixic acid was impaired in
children with Shigella gastroenteritis. 3636 Drug absorption may therefore

be decreased by very rapid gastrointestinal transit, and this effect is likely

to be most marked with poorly soluble drugs and slow release formula-
tions.
The absorption of iron, folic acid, and vitamin B E12
12 is known to be ab-
normal in patients with malabsorption syndromes, and impaired absorp-
GASTROINTESTINAL ABSORPTION OF DRUGS 913
reportedY'9. 21.42 How-
tion of penicillin, cortisol, and digoxin has also been reported.
ever, we have found that the absorption of paracetamol and
methaqualone is essentially normal in patients with malabsorption, al-
though tetracycline absorption was slightly decreased. The intestinal
bacterial flora may be abnormal in patients with malabsorption syn-
dromes, blind loops, or ulcerative colitis. Some drugs are extensively me-
tabolized by gut bacteria, and in such patients the amount of intact drug
available for absorption may be decreased. The intestinal metabolism and
absorption of salicylazosulfapyridine and L-dopa are abnormal in gno-
tobiotic animals and after treatment with antibiotics. 16 Unexplained im-
pairment of drug absorption has been observed in other disease states.
For example, the absorption of iron ascorbate is reduced in children by
fever. 1
Pharmaceutical Formulation - Bioavailability
In addition to the numerous sources of variation in drug absorption
already mentioned, further complications may arise through differences
in the absorption (bioavailability) of formulations containing the same
amount of active principle made by different manufacturers. The absorp-
tion characteristics of tablets or capsules depend on many pharmaceu-
tical factors, including particle size, the types of granulation, disintegra-
tion agents, lubricants, fillers, binders, excipients, and coatings, and the
tightness of capsule fillings and tablet compression. Adequate absorption
depends more on the way in which the product is made than on the name
of the manufacturer. Unfortunately, the elaborate in vitro disintegration
and dissolution tests of the official pharmacopeias do not guarantee ade-
quate absorption in patients. The behavior of tablets and capsules stirred
mechanically in beakers of "simulated gastric juice" is an unreliable
guide to their performance under clinical conditions.
A change from one brand of a drug to another may result in therapeu-
tic failure or unexpected toxicity as a result of differences in bioavailabil-
ity.39 The bioavailability of digoxin has recently attracted a great deal of
attention,29.43 but similar variation has been observed with many other
drugs, including anticoagulants, antibiotics, sulfonylureas, and diphenyl-
hydantoin. Enteric coated and delayed, slow, or sustained release prep-
arations should be viewed with the utmost suspicion. With a few excep-
KCI), there is rarely any need to use such formulations.
tions (e.g., KCl),
Drug Absorption Interactions
Finally, drug interactions must be considered, since multiple drug
therapy is now the rule rather than the exception. One drug may alter the
rate of absorption or the completeness of absorption of other drugs by
several different mechanisms (Table 2). Drug absorption interactions
usually result in reduced drug effects or therapeutic failure. Clinically
important interactions include reduced absorption of rifampicin and
isoniazid caused by p-aminosalicylic acid; reduced absorption of tetracy-
dines
clines taken with calcium, magnesium, aluminum and iron compounds,
and sodium bicarbonate; impaired vitamin B 12 absorption in patients with
B12
malabsorption syndromes caused by p-aminosalicylic acid and colchi-
cine; reduced absorption of thyroxine, warfarin, and other acidic drugs
914 L. F. PRESCOTT
[Link]

Table 2. Mechanisms of Drug Absorption Interactions

1. pH effects on dissolution and ionization
2. Formation of complexes and chelates
3. Changes in gastric emptying and gastrointestinal motility
4. Interference with active transport
5. Changes in membrane permeability
6. Toxic effects on gastrointestinal mucosa
7. Effects on mucosal and bacterial drug metabolism
8. Unknown

caused by cholestyramine; and increased absorption of dicoumarol and

sulfadiazine taken with magnesium hydroxide. Antacids are widely used
and can influence the absorption of drugs by effects on dissolution and
gastric emptying. 23
23 Many other drugs can alter gastrointestinal motility or

gastric emptying and cause absorption interactions. 3737 , 40

SUMMARY

The absorption of drugs from the gastrointestinal tract is a complex, .

poorly understood process which depends on many factors. The pH-parti-
tion theory of drug absorption has little relevance in clinical practice,
whereas drug dissolution, gastrointestinal motility, and the gastric emp-
tying rate are of great importance. Absorption is usually slowed and
sometimes reduced by food, but the effects are unpredictable. There is
usually marked individual variation in the rate of drug absorption, even
in fasting healthy volunteers. Drug absorption may be delayed or de-
creased in patients with gastric stasis, pyloric stenosis, gastrectomy,
malabsorption syndromes, and gastroenteritis. Additional complications
are caused by differences in bioavailability and drug interactions.

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University Department of Therapeutics

Edinburgh, EH3 94W, Scotland