Personal View
Effects of drugs on clinical laboratory tests
D S Young
From the Department of Pathology and Laboratory Medicine, University of Pennsylvania, 3400 Spruce
Street, Philadelphia. PA 19104-4283, USA
Additional key phrases: drug interferences; labora-
tory testing; clinical databases
In 1962, Caraway I highlighted the potential for
therapeutic drugs and endogenous compounds to
modify the concentrations of various analytes in
body fluids. A few years later, others, including
Elking and Kabat! and Sunderman;' amplified
Caraway's earlier report. These early papers
prompted many clinical chemists to begin to
question their test results, something that clini-
cians often did when the results did not appear to
fit the clinical picture of their patients. At the time
these papers were written there was legitimate
concern about the analytical specificity of many
laboratory methods, and clinicians did not have
confidence in the test results. The clinician's view
was that any test result that did not conform to
his or her clinical impression was erroneous.
My personal interest in the effects of drugs on
clinical laboratory tests was triggered by
physicians criticizing certain test results that
my laboratory produced. They felt that the
results were not in keeping with their clinical
impressions. They concluded the test results
were wrong. Yet I knew that quality assurance
data were within acceptable limits. Obtaining
drug histories often identified likely causes of
abnormal results. Sometimes, the clinicians were
not aware of all the in vivo effects of the drugs
they were using. It was possible to show that the
abnormal test result was related to a side-effect.
Sometimes we were able to demonstrate an
interference of a drug with an analytical method.
It seemed worth capturing the effort put into
tracking the causes of spurious results so that
other laboratory staff might find it easier to
explain unanticipated test results. The informa-
tion I accumulated was first published in a
regular issue of Clinical Chemistry.' updated in a
special issue of the journal, and then, periodi-
cally, in books published by the American
Association for Clinical Chemistry (AACC),
the most recent in 1995.5
The amount of information related to the
effect of drugs on clinical laboratory tests is
Ann Clin Biochem 1997; 34: 579-581
growing. One continuing concern is the point at
which data should be considered obsolete and
not reported. Generally, data on analytical inter-
ferences of drugs have been deleted from the
master file when references are more than 15
years old. However, for procedures that con-
tinue to be widely used, e.g. urine dipsticks, the
reported effects have been republished. In the
early editions of the publication there was con-
siderable emphasis on the effects of drugs on the
analytical methods. In the later editions there
has been less emphasis on analytical interfer-
ences as analytical specificity has improved.
In all the editions I have adopted the
philosophy that it is as important to document
that a drug has been demonstrated not to have
an effect on a particular method as it is to
describe the effects that it does have. The
clinician is often faced with an unexpected
abnormal result. He or she needs to know all
the possible causes. Invariably, clinicians are
unaware of the analytical methods used to
measure the analytes that they require to be
measured. They are also often unaware of some
of the side-effects of drugs that they use
relatively infrequently. Thus, to provide all the
information that clinicians and laboratory staff
need to properly interpret the test results, the
database of the effects of drugs must be fully
comprehensive.
A repeatedly asked question is whether the
availability of databases of effects of drugs on
clinical laboratory tests can influence medical
practice. Most users of the database can provide
anecdotal accounts of instances when it was able
to provide an explanation for unexpected
abnormal results. Shortly after the publication
of the second compilation of the database.P we
embarked on a study at the University of
Wisconsin Hospitals? to determine whether
automatic reporting to physicians of potential
drug-induced causes of abnormal test results
could modify medical practice. More than
13 000 patient-days in patients in general
surgical, minimal or moderate medical care, or
intensive care units, were followed.
579
580 Young
When an abnormal test result was obtained in
a patient receiving a drug whose presence had
been reported to affect that test, a computer
generated a report stating that the drug might
account for the abnormal result. These reports,
including the explanation of the effect in the file,
were sent with the test results to the ordering
physician. The drugs prompting most alerts were
frusemide (10'0%), acetaminophen (9'8%),
penicillin (6'5%) and hydrochlorothiazide
(4'7%). The laboratory tests most affected were
total leukocyte count (11'3%), haemoglobin
(9'0%), potassium (8'7%) and glucose (7'3%).
After the study was concluded we interviewed
the medical staff to determine the usefulness of
the program. They felt that approximately 30%
of the reports were useful and 4% actually
caused them to change the management of their
patient. Our analysis of the reports suggested
that the interaction contained in the file
provided the most probable explanation for the
abnormal test result: (a) in the general surgical
(11%); (b) minimal medical (21%); (c) moderate
medical (23%); and (d) intensive care units
(6%). Even though the file was not designed for
this application, it is reassuring that many of the
explanations were pertinent; suggesting the
potential for an automatic application of a
database to enhance medical care.
Discussions of the possible mechanisms by
which drugs affect laboratory tests have been
thoroughly documented.! It is now expected that
manufacturers will provide purchasers of their
equipment with documentation of the effects of
common drugs on the analytical methods used
in their analysers. The National Committee for
Clinical Laboratory Standards (NCCLS) has
been instrumental in developing a protocol for
manufacturers to study the effects of drugs at
physiological concentrations on the methods
included in their instruments." Such information
is invaluable. Most pharmaceutical manufac-
turers routinely provide information about the
in vivo effects of their drugs on organ function
and often document their effects on analytical
methods.
Often overlooked when assessing the effects of
drugs is the effect of metabolites of a drug that
may affect a test result to a greater extent than
the parent compound. The excipient or vehicle
in which the drug is administered, may also have
an effect unrelated to the drug itself. It would be
useful if pharmaceutical manufacturers provided
readily available documentation of both the
effects and the absence of effects of their
Ann elin Biochem 1997: 34
products on common laboratory tests. Such
information should be available from the clinical
trials prior to market release.
Both laboratory staff and clinicians must
recognize that any database of effects of drugs
on clinical laboratory tests can only provide
a possible cause of a change in a test value, not a
definitive explanation of an abnormal value in
a specific patient. Furthermore, it should be
noted that in vivo effects are usually determined
in healthy individuals, and not in patients whose
disease might influence the metabolism of the
drugs to a different extent.
Laboratory staff are now well aware of the
potential of drugs to affect the concentration of
certain analytes. However, many clinicians still
trivialize the importance of these effects, focus-
ing only on the therapeutic intent of the drug.
To enhance their role in the management of
patients, laboratory staff should think of
themselves more as an information provider
than an analyst. They should assume a consult-
ing role, providing an interpretation of the test
results. The three databases published by the
AACC now contain more than 100000 docu-
mented influences on test values.s.IO,l\ Medical
progress is such that about 10 000 new effects
are likely to accrue each year. I use an electronic
screen of the published literature, review the
abstracts of pertinent papers, and then enter
those effects (clinical, drug and pre-analytical)
that appear to be significant into a single data-
base that has been sorted, in the past, to produce
separate publications. The AACC intends to
disseminate the information electronically In
several different ways in the future.
REFERENCES
1 Caraway WT. Chemical and diagnostic specificity of
laboratory tests. Am J Clin Pathol 1962; 37: 445--{i4
2 Elking MP, Kabat HF. Drug-induced modifications
of laboratory test values. Am J Hasp Pharm 1968;
25: 484-519
3 Sunderman FW Jr. Drug interference in clinical
biochemistry. Crit Rev Clin Lab Sci 1970; 1: 427-49
4 Young DS, Thomas DW, Friedman RB, Pestaner
LC. Effects of drugs on clinical laboratory tests. Clin
Chem 1972; 18: 1041-301
5 Young DS, Pestaner LC, Gibberman V. Effects of
drugs on clinical laboratory tests. Clin Chem 1975;
21: 10-432
6 Young DS. Effects of Drugs on Clinical Laboratory
Tests. Washington, DC: American Association for
Clinical Chemistry, 1995
7 Friedman RB, Young DS, Beatty ES. Automated
monitoring of drug-test interactions. Clin Pharmacal
Ther 1978; 24: 16-21
 Effects of drugs on clinical laboratory tests
8 Forman DT, Young OS. Drug interferences In
laboratory testing. Ann Clin Lab Sci 1976; 6:
263-71
9 Powers OM, Boyd lC, Glick MR, Kotschi ML,
Letellier G, Miller WG, et al. Interference Testing
in Clinical Chemistry. NCCLS Document EP7-P, 6,
No. 13, 1986
10 Friedman RH, Young OS. Effects of Disease on
Clinical Laboratory Tests, 3rd edn. Washington,
581
DC: American Association for Clinical Chemistry,
1997
II Young OS. Effects of Preanalytical Variables on
Clinical Laboratory Tests, 2nd edn. Washington,
DC: American Association for Clinical Chemistry,
1997
Accepted for publication I July 1997
Ann Clin Biochem 1997: 34