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Drug-Lab Test Interaction - Full PDF
Drug-Lab Test Interaction - Full PDF
Drug-Lab Test Interaction - Full PDF
3
Copyright © 1976, Institute for C linical Science
ABSTRACT
C haracteristic problem s in th e interpretation of laboratory data w h en a
drug or its m etabolite interferes w ith a laboratory procedure are review ed.
Various m echanism s of interference (physical, chem ical, pharm acological
and drug-drug interaction) are discussed. T he role o f a com puterized drug-
test interference file in assisting in th e prediction as w ell as interpretation
of apparent test results is described.
TABLE I
M echanism s of Interference
Colored Urines Due to Drugs or Metabolic Disorders T here are four distinct m echanism s of
interference in laboratory testing. Physi
Color o f Urine Cause Disorder
cal, c h e m ic a l, p h a rm a c o lo g ic a l an d
drug-drug interactions are of special in
Orange-red Phenazopyridine
Phenindione
Drug related
te re st to th e lab orato ry scien tist. T he
Phensuximide m echanism s of th e interferences w ill be
briefly review ed and, w herever possible,
Red Porphyrins Congenital
porphyria
Acute
intermittant
solutions suggested.
Red-brown Hemoglobin and
porphyria
Crush
P h y s ic a l E f f e c t s
derivatives syndrome D rugs may interfere w ith colorim etric
Urobilin Hemolytic
anemia photom etric or fluorom etric analyses by
Yellow
Green-yellow
Chloroquine Drug related
im parting a characteristic color to the
specim en. In table I are described som e
Bile pigments Regurgitative
jaundice
Blue Methylene blue
Triamterene
Drug related
unusually colored urines and their rela
Blue Indigo compounds Intestinal tio n sh ip to d ru g a d m in istra tio n or
m etabolic disorders. T his type of inter
disease
(indicanemia)
Blue-green Aiaitripty 1ene Drug related
fe re n c e can b e d e te c te d v isu a lly by
laboratory person nel and drug interfer
Brown-black Melanin Malignant
melanoma
Homogentisic Acid Alkaptonuria
ences may be circum vented by collecting
th e specim en after an appropriate length
of tim e during w hich th e drug in question
pital of N orthw estern U niversity M edical has b een discontinued. T here are m any
C enter, as w ell as in som e other centers. v arieties o f drugs an d foods th a t can
A major problem facing users of the cause th is ty p e of in terference. T h ese
various collations of laboratory test inter should be co n sid ered first as possible
ferences is the relationship betw een drug causes of any unusually colored urine.
dosage and diagnostic test interference Som e drug s act as in d icato rs (e.g.,
and the possible synergistic effect of sev p h e n o lp h th a le in , v eg etab le laxatives)
eral drugs. T he m etabolic and clinical and affect tests carried out at a particular
states of the patien t also affect the degree pH . T he p resence of sulfobrom ophtha-
of laboratory in terferen ce. If an in d i lein dye (BSP) in serum w ill interfere
vidual has norm al kidney and liver func w ith serum protein determ in ed by the
tion, the response w ill be different to a b iu ret m ethod. T h e dye is colorless at the
drug dosage than that of th e patien t w ho pH of blood b u t pu rp le w hen m ade al
is unable to detoxify or to excrete the kaline during th e assay.
com pound. C h e m ic a l E f f e c t s
D rugs m ay b e m easured as analytes,
In order to cope w ith the problem of e ith e r b e c a u se o f th e ir sim ila rity in
drug induced m odifications of laboratory chem ical structure or because they con
test values, laboratory scientists should tain a com ponent th at is an analyte. P a
possess an understanding of th e m ech tients w ho have receiv ed radiographic
anism s involved in these interferences. con trast m ed ia co n tain in g io dine w ill
T he purpose of this article is to consider have an altered protein-bound iodine, al
these m echanism s and to discuss the role though thyroxine is not affected w hen d e
of the com puterized drug-test interference term in ed by protein bin d in g m ethods.
file in the prediction as w ell as the inter T he m ost serious and long-lasting inter
pretation of apparent test results. ferences are those caused by intraven
DRUG INTERFERENCE IN LABORATORY TESTING 265
ously adm inistered iodinated radiopaque sp e c ific e n z y m a tic g lu co se-o x id ase
agents (e.g., acetrizoate and adipiodone). m ethod is em ployed, ascorbic acid can
T he drugs orabilex and dionsil have a cause a false negative result by preven t
negligible effect on th e analysis of pro ing the oxidation o f a specific chrom ogen
tein b o un d iodine at a concentration no in the reaction.
greater than 100 fig p er dl, b u t seriously Increased transam inase activity has
affect the procedure at 1000 fig per dl. been observed w hen the diazocolorim et-
Serum potassium concentration is in ric m ethod is used. U nusually increased
creased by the concurrent adm inistration activity has b een reported in patients
of intravenous potassium penicillin G. w ith ketosis and also in patients receiv
T he penicillin preparation contains 1.7 ing erythrom ycin 13 or p-am inosalicylic
m m ol o f potassium per m illion units. acid .9 T hese test interferences can be ob
Thus, a patien t receiving 10 m illion units viated by em ploying ultraviolet kinetic
of th e antibiotic receives 17 m m ol (m Eq) procedures.
o f potassium . C olorim etric procedures u sed in steroid
A chem ical interference m ay also result assays are often subject to drug interfer
w hen the substance b eing determ ined e n ce . In th e d e te rm in a tio n o f 17-
reacts in vivo w ith a drug adm inistered ketosteroids by th e Z im m erm an reaction,
prior to th e collection of blood for drugs w ith th e 17-keto basic structure,
analysis. F or exam ple, serum calcium de such as ascorbic acid, m orphine and re-
term inations m ay be affected by the ad serpine, w ill cause increased values. In
m in istratio n of th e ch elatin g agent, th e determ ination of 17, 21-dihydroxy-
ethylenediam inetetracetate (ED TA ).3 In steroids by the Porter-Silber reaction, the
certain conditions such as lead poisoning dihydroxyacetone chain is th e reactive
and collagen disease, E D T A has b een unit. D rugs like m eprobam ate, chloral hy
used therapeutically to reduce th e lead drate, chlorprom azine and potassium io
and calcium concentrations, respectively. dine w ill interfere w ith this reaction and
Less w ell recognized is th e fact th at vari cause elevated values. In the colorim etric
ous chelating agents are also used as p re determ ination of vanillylm andelic acid
servatives to p reven t oxidation reactions (VMA) by a diazo reaction, drugs like
in drug preparations. In patients on m ethocarbam ol and m ethyl dopa cause
ED TA therapy, calcium cannot be de falsely elevated results.
term ined by the indirect colorim etric or W hen specific drugs have b een dem
fluorom etric m ethods based on th e chela onstrated to interfere w ith chem ical
tion o f a calcium —E D T A com plex. H ow reactions, patients should be m aintained
ever, in calcium d eterm in atio n s by free of these drugs for at least 72 hours
ato m ic-ab so rp tio n sp ectro sco p y , th e before collecting the specim en. O ther
com plexing agent is destroyed in the an aly tical te c h n iq u e s, e.g ., co lu m n
flam e and th e direct concentration of cal chrom atography and radioim m unoassay
cium can be determ ined. procedures, can also be subm itted for an
D rugs can also interfere w ith labora affected m ethod.
tory results by negating certain non
specific oxidation and reductions essen Pharm acological Effects
tial for the chem ical assay. Penicillin, This type o f interference usually re
strep to m y cin an d ascorbic acid are sults from the pharm acological or toxic
know n to react w ith cupric ion; thus, false activity of drugs b u t m ay also arise from
positive results for glucose may occur if a th erap eu tic q u an tities of drugs. An
copper reduction m ethod is used. If the exam ple is the increase in prothrom bin
266 FORMAN AND YOUNG
TABLE II
and diabetics m ay require m ore insulin
Drugs Capable of Increasing Blood Glucose or oral antidiabetic drugs. Patients w ith
latent diabetes occasionally develop an
Dextrothyroxine Phenothiazines abnorm al glucose tolerance curve. Salicy
lates have also b een reported to reduce
Diazoxide Steroids
Diphenylhydantoin Adreno cort icos teroids
Diuretics
Nicotinic acid
Estrogens
hyperglycem ia in diabetics and produce
hypoglycem ia in norm al children. In ta
Sympathomimetic amines
Plasma cortisol 15.0 ± 4.0 yg/dl 40.0 ± 11 yg/dl fects un related to th eir therapeutic ac
(8:00 A.M.) tions. Inheritance of hem oglobins differ
Serum thyroxine
Urinary 17-OH
6.6 ± 1.4 yg/dl
4.6 ± 1.1 mg/d
9.4 ± 1.7 yg/dl
2.6 ± 0.9 mg/d ing in structure from norm al hem oglobin
corticosteroids
Estrogens, total 40.0 ± 18 yg/d
A is w ell described. All types of hem o
globin are oxidized to m ethem oglobin by a
26.0 ± 7.4 yg/d
(urine)
Vanilmandelic
acid (urine)
3.5 ± 1.6 mg/d 3.3 ± 1.6 mg/d
w ide range of agents and about 1 percent
o f hem oglobin present in the blood of
*Lucis, O.J. and Lucis, R. : Bull. WHO 46:443, 1972. norm al peo ple is in this form. M any drugs
DRUG INTERFERENCE IN LABORATORY TESTING 267
slightly increase th e am ount of m ethem o- TABLE VI
T A B L E VII
tethim ide and haloperidol are know n to can be accepted or rejected b y the pa
in h ib it the effectiveness of w arfin therapy tien t’s physician on th e basis of his clini
by this m echanism .7 T hese drug-drug cal ju d g m en t
interactions may result in a redic ed pro- O ur experience in a university teaching
tlr on b in tin e. E nzyn e inhibition is hospital, in w hich over 10,000 patient-
another resu lt of drug-drug interaction days w ere m onitored, indicated th at the
an d the in paim e n t of the hepatic glicur - drug file provided the correct explanation
onyl transferase system by phenothiazine for changes in laboratory data in approx
derivatives is a good exam ple. W henever im ately 21 p ercent of all the occasions in
several dru gs are adn in istered c oncug w hich a report was produced .21 A report,
rently to a patient, th eir com bined effect sim ilar in con ten t and form at to an entry
on laboratory results should be carefully in the m aster file ,20 was generated w hen
considered. an abnorm al test resu lt was produced and
one of th e adm inistered drugs had b een
E ffectiveness of C om puterized D rug described as causing th e effect. T he yield
Interference F ile of correct explanations w ould undoub
T he com puterized drug interference tedly be increased by elim ination of ef
file has b e e n used in tw o m odes. In one, fects th at w ere unlikely to arise in hospi
possible interactions are listed in re tal practice, e.g., effects ow ing to over
sponse to direct queries (the role for doses or toxic effects of drugs. To m ake it
w hich it was originally designed). In the appropriate for on-line use in any particu
other, th e file has been used to provide lar hospital, the file should be m odified
autom atic interpretation of effects of to elim inate these effects. T he only
drugs on tests. In this m ode, the file is m ethodological interferences that should
used to provide a report alerting a physi be in clu ded are those involving the pro
cian to a possible interaction betw een a cedures in use in the hospital laboratory.
drug and a test (figure 1). W ithout a com T he file is being m odified for use in the
puterized hospital inform ation system, autom atic w arning role in a com m unity
w hich could be accessed to provide in hospital to determ ine if it can provide a
form ation about a patien t’s clinical state useful service for physicians w ith a differ
and nontherapeutic-drug procedures, the ent orientation from those in a university
drug file cannot be com pletely effective hospital.
in providing explanations for changes in In the off-line m ode of use of the drug
laboratory data. Its role m ust be that of a file, the data-base, stored in a tim e-shared
w arning system to highlight possible com puter, is interrogated through a re
causes o f changes in test values w hich m ote device such as a cathode-ray term i-
DRUG INTERFERENCE IN LABORATORY TESTING 269
DRUG EFFECTS 10/23/75
PATIENT ID. 086-24-095
PATIENT NAME ROBERT STAR
ROOM NUMBER 4102
DOCTOR GUTHRIE
DRUG: HEPARIN
nal. T he questions th at may be asked in tive search routine. This m ode of opera
clude all the effects of a drug, all the tion is in use only at the N ational Insti
drugs that affect a test or, m ore specifi tutes o f H ealth, (NIH ) and a sim pler
cally, does a particular drug affect a par procedure is used in E vanston H ospital.
ticular test procedure by a particular T he m ost im portant use of a com puter
m echanism . In each of these situations it in setting up the CLA U D E (Com puter
is possible to list th e appropriate litera L isting o f A bnorm al and U sual D rug E f
ture reference. T he search procedure has fects) concept may be th at of a text editor
b een designed in an interactive m ode so and sorter. Scanning a printout is m uch
th at even an individual w ho has never m ore efficient than searching the file in
used it may obtain an explanation for a the com puter, except for any inform ation
particular problem , b u t the exp erienced that is not yet available on a printout. It is
searcher can by-pass th e longer interac our intention to reproduce printouts of
270 FOBMAN AND YOUNG
th e file in a journal w ith a w ide circula w ere avoided ow ing to the sim ple expla
tion to th e appropriate audience w h en a nations provided by the file. It is ex
significant am ount o f new inform ation p ected th at the application o f th e file w ill
has b e en added to th e m aster-file. T he be expanded by introducing it in a re
second edition has recently b een p u b vised form into several hospitals for on
lish ed .22 It includes som e inform ation on line interpretation of data. Also, discus
th e probabilities of certain effects occur sions have b e e n h eld w ith several
ring, as w ell as an indication of the con different institutions overseas to set up
centration of drug at w hich th e effects national centers for dissem ination of in
occur, at least for the m ethodological form ation and to provide better m onitoring
effects. of foreign language publications to aug
T he file is used routinely in the m ent th e content of the file.
laboratory at N IH in an attem pt to explain
abnorm al te st resu lts. T he re sid e n t R eferences
physicians affiliated w ith th e clinical 1. BORUSHEK, S. and GOLD, J.: Com m only used
chem istry service discuss the results w ith m edications that interfere w ith routine endo
crine laboratory procedures. C lin. Chem .
the patient-care physicians to determ ine 20:41-52, 1964.
if the results w ere due to the patien t’s 2. C araway , W. T.: Chem ical and diagnostic
clinical state or to a drug effect. This specificity of laboratory tests. Amer. J. Clin.
Pathol. 37:445-464, 1962.
close m onitoring of test results has led to 3. C arr , M. H. and F rank , H. A.: Calcium
recognition of deficiencies in w hat is b e analysis in patients being treated w ith EDTA.
lieved are specific enzym atic procedures C lin. Chem . .3:20-21, 1957.
4. COHON, M. S.: D rug interactions involving
for the m easurem ent of glucose and uric levodopa. Rev. D rug Interactions 1 :45-62,
acid. L ikew ise, th e guaiac procedure for 1974.
occult blood in feces was found to yield 5. C o nn ery , A. H .: Pharm acological im plications
of microsomal enzym e induction. Pharm . Rev.
false negative results un d er certain cir 29:317-366, 1967.
cum stances. T his has prom pted the de 6. D ubois , E. L., T allm an , E., and W onka , R.
velopm ent of a m ore specific procedure A.: C hloroprom azine-induced system ic lupus
erythem atosis. J.A.M.A. 222:595-596, 1972.
(Jaffe e t al. unpublished). 7. E b e r t , R.: Oral anticoagulants and drug in
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questions from clinical staff at N IH , to 1968.
8. ELKINS, M. P. and Kabat , H. F.: D rug induced
physicians and to laboratory scientists modifications of laboratory test values. Amer. J.
throughout the country w ho subm it th eir H osp. Pharm. 25:484-519, 1968.
problem s by letter or telephone. T he file 9. G l y n n ,K. P., C a r f a r o ,A. F., F o w l e r ,C. W.,
and STEAD, W. W.: False elevations o f serum
has b een u sed to provide inform ation for glutam ic oxaloacetic transam inase due to
a pharm aceutical m anufacturing com paraam inosalicylic acid. Ann. Intern. M ed.
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10. L it tl e , D. M. and E s t s t o n e , H. J.: Anaes
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12. LuClS, O. J. and Lucis, R.: Oral contraceptives
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DRUG INTERFERENCE IN LABORATORY TESTING 271
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