CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2004;2:725–730
REVIEWS
Drug Interactions in Gastroenterology: Mechanisms,
Consequences, and How to Avoid
LAURENCE J. EGAN
Gastroenterology Research Unit, Mayo Clinic, Rochester, Minnesota
Drug interactions are an important avoidable cause of
illness. With an increasing array of medications avail-
able to treat human disease and an increasing number
of patients taking many medications, the risk of clini-
cally significant drug interactions increases. This review
describes some examples of common drug interactions
in gastroenterology. The underlying mechanisms are dis-
cussed, and strategies are proposed to avoid drug inter-
actions in clinical practice.
very year, the arsenal of medications available to
E treat human disease becomes greater. This is cer-
tainly the case in gastrointestinal and liver diseases, in
which exciting novel therapeutics are improving the lives
of patients with inflammatory bowel disease, gastroin-
testinal motility disorders, and hepatitis C to name but
a few examples. Optimum management of many diseases
treated by gastroenterologists requires the use of more
than one drug, and with advancing age, many of our
patients have additional diseases that require drug ther-
apy. Recent U.S. data indicate that almost 90% of indi-
viduals older than 65 years take regular prescription
medications, and that people aged 50 – 64 years fill an
average of 13 prescriptions per year, whereas those older
than 80 years fill an average of 22 prescriptions in 1
year.1 In Sweden, a study of more than 5000 elderly
outpatients showed that the average number of prescrip-
tion medications taken by individuals in this demo-
graphic group was more than 5.2
With individual patients taking such large numbers of
drugs comes the increased likelihood of unanticipated
and unwanted clinical responses to drug combinations
that differ from the known effects of the drugs when
given alone. This review article provides examples of
such drug interactions that occur commonly in gastro-
enterologic practice. The consequences of these interac-
tions are shown, and the biological mechanisms that
cause the unwanted effects are also explained. Most sig-
nificant drug interactions are caused by a relatively small
number of mechanisms, often by affecting the absorp-
tion, distribution, metabolism, or excretion of the drug.
Knowledge of the underlying mechanism can be used to
predict and prevent similar interactions between other
drugs. Individuals who have inherited drug metabolizing
enzymes of low activity as a result of genetic polymor-
phisms of the genes encoding those enzymes might be
predisposed to interactions when they take drugs that are
inactivated by that enzyme. Finally, general strategies are
proposed to avoid the occurrence of clinically significant
drug interactions.
Case 1: Reduced Intestinal
Absorption
A 31-year-old man with advanced human immu-
nodeficiency virus infection complicated by disseminated
histoplasmosis was receiving maintenance itraconazole.
He developed symptoms of gastroesophageal reflux.
Omeprazole, a proton pump inhibitor, was prescribed.
After 7 days of omeprazole therapy, the patient experi-
enced a recrudescence of previously controlled histoplas-
mosis. Blood itraconazole levels were found to be sub-
therapeutic.
What happened? Omeprazole therapy dramatically re-
duced gastric acid production and controlled symptoms
of heartburn. However, absorption of itraconazole, which
depends on an acidic environment in the upper gastro-
intestinal tract, was significantly reduced in the presence
of impaired gastric acid production, resulting in sub-
therapeutic blood levels (Figure 1).3
Case 2: Reduced Renal Excretion
A 60-year-old woman was in a stable remission of
Crohn’s disease on treatment with weekly subcutaneous
methotrexate injections. She developed arthralgias that
did not improve with acetaminophen, so she self-medi-
© 2004 by the American Gastroenterological Association
1542-3565/04/$30.00
PII: 10.1053/S1542-3565(04)00343-X
726 LAURENCE J. EGAN
Figure 1. The omeprazole-itraconazole interaction is caused by a
pharmacokinetic mechanism at the level of itraconazole absorption.
cated with over-the-counter ibuprofen, which she took
on a daily basis. After 4 weeks, she became fatigued and
developed a fever and cough. Work-up showed pneumo-
nia caused by Pneumocystis carinii infection. Hematologic
analysis showed a leukocyte count of 0.9 ⫻ 109 per liter.
Injections of fully reduced tetrahydrofolate (leucovorin)
resulted in a prompt recovery of the leukocyte count to
normal.
What happened? Methotrexate is mostly eliminated by
active renal tubular secretion into the urine. Ibuprofen
decreases the excretion of weak acids, resulting in the
retention of methotrexate and bone marrow suppression
that can be reversed by administration of leucovorin
(Figure 2).4
Figure 2. The methotrexate-ibuprofen interaction is caused by a phar-
macokinetic mechanism at the level of methotrexate excretion.
CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 2, No. 9
Figure 3. The cyclosporine– grapefruit juice interaction is caused by a
pharmacokinetic mechanism at the level of cyclosporine first-pass
metabolism.
Case 3: Reduced First-Pass
Metabolism
A 44-year-old woman was doing well 2 years after
orthotopic liver transplantation on cyclosporine-based
immunosuppression. She became concerned about low
vitamin C intake, so she began to consume a large glass
of grapefruit juice every morning. After 7 days she
developed headaches and became tremulous. Her blood
pressure measurements and serum creatinine level were
found to be elevated. Blood cyclosporine concentration
was 450 ng/mL, well above the therapeutic range. Tem-
porary cessation of cyclosporine until the blood concen-
tration normalized resulted in clinical resolution.
What happened? A constituent of grapefruit juice de-
creases the expression of intestinal cytochrome P450
isoform 3A4 activity, a major pathway of cyclosporine
inactivation.5 This leads to dramatically reduced first-
pass metabolism of cyclosporine and results in elevation
of blood cyclosporine concentration and consequent
symptoms of toxicity (Figure 3). A similar decrease in
cyclosporine inactivation occurs when it is co-adminis-
tered with another cytochrome P450 3A4 inhibitor,
ketoconazole. In fact, the concomitant administration of
ketoconazole has been proposed as a way to decrease the
dose of cyclosporine needed to prevent transplanted or-
gan rejection.6
Case 4: Reduced Inactivation
A 71-year-old man was in a stable condition
taking azathioprine for Crohn’s disease, when he devel-
September 2004
Figure 4. The azathioprine-allopurinol interaction is caused by a phar-
macokinetic mechanism at the level of azathioprine metabolism.
oped acute gout. After the acute attack subsided, the
xanthine oxidase inhibitor, allopurinol, was prescribed to
prevent recurrences of gout. Two weeks later, the patient
visited his physician because of fatigue, and a blood
count showed a leukocyte count of 1.1 ⫻ 109 per liter,
along with marked anemia and thrombocytopenia. Tem-
porary cessation of azathioprine was followed by normal-
ization of hematologic parameters.
What happened?Allopurinol inhibits xanthine oxidase,
the rate-limiting enzyme of one of the chief metabolic
pathways available for azathioprine metabolism.7,8 As a
result, a greater proportion of the drug undergoes con-
version to 6-thioguanine, the active metabolite of aza-
thioprine. This results in excessive bone marrow suppres-
sion by 6-thioguanine nucleotides (Figure 4).
Case 5. Increased Hepatic
Inactivation
A 46-year-old woman with a history of spontane-
ous acute mesenteric vein thrombosis was found to have
the Factor V Leiden mutation, and lifelong warfarin was
recommended. She took a steady dose of warfarin. Later,
she experienced an acute epileptic seizure, and phenobar-
bital was administered. Two weeks later, she developed
acute abdominal pain and was found to have a recurrence
of acute mesenteric vein thrombosis. Her international
normalized ratio was 1.0.
What happened? Phenobarbital induces the expression
of certain hepatic cytochromes P450, resulting in in-
creased inactivation of drugs that are metabolized by
these enzymes, such as warfarin.9 Consequently, the an-
ticoagulant activity of warfarin was diminished, predis-
posing this patient to recurrent spontaneous thrombosis
(Figure 5).
DRUG INTERACTIONS IN GASTROENTEROLOGY 727
Case 6: Synergistic Effects
A 61-year-old woman was taking warfarin for
chronic atrial fibrillation. She developed joint pain and
self-medicated with aspirin. Seven days later she had
melena and was found to have several small gastric
erosions that were oozing blood. Hematologic evaluation
was normal apart from an international normalized ratio
of 2.0.
What happened? Both warfarin and aspirin decrease the
ability of the blood to clot, but by different mechanisms.
Warfarin inhibits production of vitamin K– dependent
factors in the clotting cascade, whereas aspirin inhibits
platelet function. Therefore, in combination, their anti-
coagulant effects are synergistic and in this case resulted
in excessive loss of normal hemostatic mechanisms.10
Aspirin can also injure the gastric mucosa, which likely
contributed to the bleeding in this case (Figure 6). Both
warfarin and aspirin are heavily plasma protein bound, so
the addition of aspirin to regular warfarin therapy might
displace warfarin from plasma protein binding, resulting
in a temporary increase in free plasma warfarin. However,
the warfarin displaced from binding to plasma proteins
by aspirin is rapidly distributed and metabolized, so
equilibrium is reestablished with very similar amounts of
free drug in plasma. The lack of elevation of international
normalized ratio above therapeutic levels in this case
shows that this pharmacokinetic mechanism was not an
important contributor to this interaction.11
Case 7: Antagonistic Effects
A 55-year-old man with cirrhosis of the liver and
portal hypertension had ascites that was well-controlled
on a low-sodium diet and stable doses of spironolactone
Figure 5. The warfarin-phenobarbital interaction is caused by a phar-
macokinetic mechanism at the level of warfarin inactivation.
728 LAURENCE J. EGAN
Figure 6. The warfarin-aspirin interaction is caused by a combination
of pharmacodynamic mechanisms that result in greater anticoagulant
effects.
and furosemide. He developed painful osteoarthritis of
the knees and self-medicated with over-the-counter in-
domethacin. After a few days, he noticed a gradual
recurrence of leg edema, abdominal fullness, and weight
gain. Examination confirmed the presence of ascites.
What happened? The cirrhotic state causes intense so-
dium retention by the kidneys, which in many patients
must be counterbalanced by diuretic therapy to promote
sodium excretion. Nonsteroidal anti-inflammatory drugs
such as indomethacin inhibit the production of prosta-
glandins in the kidney, which are essential for mainte-
nance of adequate glomerular filtration rates. In this case,
the natriuretic effects of diuretics were negated by re-
duced renal blood flow caused by lowering of prostaglan-
din levels by indomethacin, resulting in sodium and
water retention (Figure 7).
Figure 7. The furosemide-indomethacin interaction is caused by a
pharmacodynamic mechanism at the level of renal sodium handling.
CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 2, No. 9
Figure 8. The cause of the selegiline-meperidine interaction is
obscure.
Case 8: Idiosyncratic Interaction
A 71-year-old man with Parkinson’s disease was
being treated with selegiline, a monoamine oxidase in-
hibitor. He presented for colonoscopy and received con-
scious sedation, which included meperidine. During the
procedure, the patient’s blood pressure increased dramat-
ically; he became febrile and had a tonic-clonic seizure.
What happened? This is an example of an idiosyncratic
drug reaction in which 2 co-administered drugs cause a
severe effect that is not typical for either drug alone
(Figure 8). This interaction can occur when other mono-
amine oxidase inhibitors are co-administered with several
opiates.12
Drug Interactions: Basic
Mechanisms
As illustrated in these examples, one drug or a
foodstuff can interact with another drug by affecting its
absorption, distribution, metabolism, or excretion, so-
called pharmacokinetic interactions. In these types of
interactions, the concentration of drug at the effect site is
altered, producing either excessive or inadequate effects
that generally can be predicted on the basis of the known
effects of the drug. For these types of interactions to be
clinically significant, the drug whose effect is altered
must have a narrow therapeutic window, i.e., the con-
centration range within which the drug is effective but
not toxic must be small. Many drugs have very wide
therapeutic windows and thus are intrinsically unlikely
to be involved in clinically significant drug interactions
based on pharmacokinetics. Another prerequisite for
drug interactions of the pharmacokinetic type to reach
clinical significance is the presence of a steep dose-
September 2004
Table 1. Some Important Inducers of Cytochromes P450
and Commonly Affected Drugs
Common P450 inducers (P450 affected)
Ethanol (2E1)
Carbamazepine (3A4, 5, 7)
Phenobarbital (2B6, 3A4, 5, 7)
Phenytoin (3A4, 5, 7)
Rifampicin (2C9)
Commonly affected drugs (P450 involved)
Warfarin (2C9)
Corticosteroids (2C19)
Cyclosporine (3A4)
Birth control pills (3A4)
response curve for the affected drug, that is, there is a
large difference in effect with a relatively small difference
in drug concentration. If sharp changes in drug concen-
tration induced by an interacting drug do not signifi-
cantly affect the responses caused by that drug, then the
interaction is unlikely to be noticed.
Of particular importance in pharmacokinetic drug
interactions are the inducers and inhibitors of hepatic
microsomal cytochromes P450. These are the heme-
containing enzymes responsible for inactivation of the
majority of xenobiotic substances (exogenous chemicals),
including drugs that we encounter in our lives. The
expression levels of various cytochromes P450 are in-
creased by certain drugs, leading to the presence of
greater enzymatic activity and consequently faster rates
of inactivation of the drug substrates for the induced
enzyme (Table 1). This can lead to lower drug concen-
trations and loss of effect. Conversely, certain drugs tend
to inhibit the activity of cytochromes P450 and conse-
quently increase the concentration of drugs that are also
inactivated by the inhibited cytochrome P450 (Table 2).
In many drug interactions that are due to a reduction in
the rate of inactivation, the interacting drugs are both
substrates for the same cytochrome P450. In this situa-
tion, the drug with the lower affinity for the enzyme will
be metabolized more slowly than the drug with high
affinity, leading to an elevation in the concentration of
that drug. Many drugs can be metabolized by more than
one member of the cytochrome P450 family, so reduced
access to the usual route of inactivation might be partly
compensated by the action of another enzyme with a
lower affinity for that drug, thus reducing the impact of
the interaction. The low substrate specificity of cyto-
chromes P450 and the resulting redundancy in pathways
of xenobiotic detoxification might represent an evolu-
tionary mechanism of resistance to the potentially harm-
ful effects of environmental toxins that we encounter,
including drugs.
It has been recognized for decades that an individual’s
capacity to metabolize certain drugs is an inherited
DRUG INTERACTIONS IN GASTROENTEROLOGY 729
trait.13 Thus, in a population, one can identify groups of
people who have low, intermediate, or high capacity to
metabolize a drug or a class of drugs. In the genomic era,
it has become clear that this variation is due to polymor-
phisms (common natural variations) in the sequences of
genes encoding the enzymes that metabolize drugs. Gen-
erally, if an individual inherits 2 normal copies of the
gene, they have high activity of the encoded enzyme;
with 1 normal and 1 abnormal copy, they have interme-
diate activity; and with 2 abnormal copies they have low
or absent activity. Individuals who inherit low activity of
a drug metabolizing enzyme are at increased susceptibil-
ity for clinically significant drug interactions when they
take a drug that is metabolized by that enzyme. Cur-
rently, testing for polymorphisms of drug metabolizing
enzymes is clinically available only for a very small
number of enzymes, such as thiopurine methyltrans-
ferase.13 However, in the near future, the ability to
individualize drug therapy on the basis of genetic poly-
morphisms might be one of the first clinical payoffs of
genomics, so-called pharmacogenomics.
Pharmacodynamic drug interactions are those in
which the effect of a drug is modified by another drug
that does not affect the concentration of the other. In-
teractions of this type primarily occur when drugs with
synergistic or antagonistic affects are co-administered.
Clinically significant idiosyncratic drug interactions are
fortunately quite rare, because the drugs that are suscep-
tible to such interactions are recognized as being less safe
than alternative counterparts for given indications.
Drug Interactions: How to Avoid
The busy practicing physician must develop strat-
egies that promote safe prescribing habits. One element
of safe prescribing is to be alert to potential interactions
between medications that the patient is already taking
and the new drug being considered. First and foremost,
polypharmacy must be avoided whenever possible. The
potential for clinically significant drug interactions in-
creases with the number of medications being taken, so
a careful periodic review of the list of medications being
taken by the patient is important, and every opportunity
should be taken to discontinue unnecessary medica-
Table 2. Some Important Inhibitors of Cytochromes P450
Cytochrome P450 Inhibitor Affected drug
3A4 Erythromycin Cyclosporine
3A4 Ritonavir Saquinavir
3A4 Cimetidine Amiodarone, phenytoin
1A2 Ciprofloxacin Theophylline
2C9 Isoniazid Warfarin
730 LAURENCE J. EGAN
Table 3. Strategies to Avoid Significant Drug Interactions
Strategy
Identify high risk Elderly
patients Critically ill
HIV infection
Identify high risk Drug metabolizing enzyme inducers and
drugs inhibitors
Drugs with narrow therapeutic window
Drugs with serious adverse effects
Drugs with known idiosyncratic interactions
Check current Avoid unnecessary polypharmacy
medications
Consultation Pharmacist
Electronic database, e.g., Micromedex,
ePocrates
Websites, e.g., http://www.drugdigest.org/
DD/Interaction/ChooseDrugs, http://
medicine.iupui.edu/flockhart/
HIV, human immunodeficiency virus.
tions.2,14 Special care must also be taken to ascertain
whether the patient takes any over-the-counter or “alter-
native” medications. Pharmacists routinely evaluate po-
tential drug interactions, but they might not be aware of
all drugs taken by the patient. Individual patients at
high risk for drug interactions should be recognized.
Groups who have been identified as being at high risk for
drug interactions include the elderly, the critically ill,
and human immunodeficiency virus–infected patients.15
Extra caution should be exercised in these patient groups
when prescribing new medications. The safety profiles of
the drugs taken by the patient should be known. As
discussed above, many drugs are relatively unlikely to be
involved in clinically significant drug interactions,
whereas others with more narrow therapeutic windows or
more serious potential adverse effects must be more
closely evaluated. Drugs that induce or inhibit the cyto-
chrome P450 system are particularly important, because
they can affect the metabolism of many other drugs.
Conclusion
In summary, understanding the principles and
mechanisms of drug interactions will allow the prescriber
to recognize situations in which clinically significant
interactions are most likely to occur. A number of useful
electronic resources are available to physicians and pa-
tients to check on potential drug interactions (Table 3).
If in doubt, consultation with a pharmacist will allow the
CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 2, No. 9
prescriber to obtain the latest information on a potential
interaction and to evaluate alternative therapies that
might be more suitable.
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Address requests for reprints to: Laurence J. Egan, M.D., Gastroen-
terology Research Unit, Mayo Clinic, 200 First Street S.W., Rochester,
Minnesota 55905. e-mail: egan.laurence@mayo.edu; fax: (507) 255-
6318.
The author thanks Dr. Dennis Mays for helpful comments and
Deborah Frank for secretarial assistance.