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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 drugtest interference file in assisting in th e prediction as w ell as interpretation
of apparent test results is described.
Introduction
tic le on th e ch em ical an d d iag n o stic
O ver th e past decades, the practice of specificity of laboratory tests. In 1964,
m ed icin e has u n d erg o n e con sid erab le B orushek and G old 1 published an article
sophistication. P otent new drugs in prac containing a list of drugs interfering w ith
tically every therapeutic category are avail routine endocrine procedures. W irth and
able. W henever a patient receives a T hom pson ,19 in 1965, pu blished a list o f
drug, there is a possibility of drug-test in substances and conditions w hich affect
terferences. W hen m ore than one drug is th e re su lts o f lab o rato ry p ro c e d u re s.
adm inistered, th ere m ay also be drug- T hey included such factors as tem pera
drug interactions. T hese developm ents ture, light and drugs. O ther review artih av e c re a te d n ew p ro b le m s for th e cles 8,11,14,17 have b een of great value in
laboratory scientist. A characteristic prob helping to define this problem .
O ne of the m ost am bitious approaches
lem is th e in terp retatio n o f laboratory
to
this problem has b een the develop
data w hen a drug or its m etabolite may
m
ent
of a 9000-entry com puter-file based
in terfere w ith a laboratory proced ure.
O ne drug m ay affect the action o f another on a compilation of 1030 literature refer
given at the same tim e, thus changing the ences .20 This com puterized com plication
of effects of drugs on laboratory tests has
value of a test result.
N um erous attem pts have b een m ade b een used to assist in th e interpretation
by a num ber of com pilations and articles o f u n u su al te st resu lts in th e clinical
to d o c u m e n t th e s e effe c ts. In 1962, chem istry laboratories of th e N ational In
Caraw ay 2 pu blished a com prehensive ar stitutes of H ealth and the E vanston Hos263
264
Color o f Urine
Orange-red
Red
Cause
Phenazopyridine
Phenindione
Phensuximide
Porphyrins
Red-brown
Hemoglobin and
derivatives
Urobilin
Yellow
Green-yellow
Chloroquine
Bile pigments
Blue
Blue
Methylene blue
Triamterene
Indigo compounds
Blue-green
Brown-black
Aiaitripty 1ene
Melanin
Homogentisic Acid
Disorder
Drug related
Congenital
porphyria
Acute
intermittant
porphyria
Crush
syndrome
Hemolytic
anemia
Drug related
Regurgitative
jaundice
Drug related
Intestinal
disease
(indicanemia)
Drug related
Malignant
melanoma
Alkaptonuria
M echanism s of Interference
T here are four distinct m echanism s of
interference in laboratory testing. Physi
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
te re st to th e lab orato ry scien tist. T he
m echanism s of th e interferences w ill be
briefly review ed and, w herever possible,
solutions suggested.
P h y s ic a l E f f e c t s
265
266
Dextrothyroxine
Diazoxide
Diphenylhydantoin
Diuretics
Nicotinic acid
Phenothiazines
Steroids
Adreno cort icos teroids
Estrogens
Sympathomimetic amines
TABLE III
Drugs Capable of Decreasing Blood Glucose
Alcohol
Asparaginase
Caffeine
Haloperidol
Level in
Menstruating
Women
Level in Women
on Oral
Contraceptives
40.0 11 yg/dl
9.4 1.7 yg/dl
2.6 0.9 mg/d
26.0 7.4 yg/d
3.3 1.6 mg/d
267
TABLE VI
slightly increase th e am ount of m ethem oDrugs Inducing Hepatic Microsomal Enzymes
globin, even in norm al individuals, b u t
induce a striking and som etim es fatal
Barbiturates
m ethem oglobinem ia in susceptible pa Phenylbutazone
Glutethimide
Cortisone
Chlordiazepoxide
tients. T hese drugs include chlorates, Aminopyrine
Testosterone
sulfonam ides, nitrites, quinones, acetan- Diphenylhydantoin
Norethynodrel
Carbutamide
ilid and acetophenetidin. A sim ilar p h en
om enon occurs w ith prim aquine sensitiv
ity. Susceptible patients have an in herited tisol and decrease the concentration of
defect in red cell glucose 6 -phosphate de cortisol in th e plasm a.
A dverse side reactions m ay also occur
hydrogenase (G 6 -PD ) an d develop a se
w
ith
pharm acologically active drugs.
vere hem olytic anem ia w hen exposed to
M
any
drugs have b een associated w ith
prim aquine.
inducing
abnorm al liver, renal an d p u l
A nother abnorm al drug response is
m
onary
function
.10 T hese drug-test ef
porphyria. A cute porphyria on exposure
fects
are
unexpected
and should be rec
to drugs can be caused by sudden m as ognized. D rugs in this
group include
sive induction o f deltaam ino levulinic m ethyltestosterone, reserpine,
phenaceacid synthetase in hepatic m itochondria
m
ide,
oxyphenylbutazone,
anesthetics
w hich results in uncontrolled form ation
a variety of cancer chem otherapeutic
of porphobilinogen and its m etabolites. and
agents.
S usceptibility is in herited as an au
tosom al dom inant trait and occurs even in D rug-D rug Interactions
heterozygotes. T he nature o f th e m olecu
D rugs w hich in dep end ently have little
lar defect is unclear and presum ably lies effect on laboratory tests m ay interact to
in the repression m echanism for the gene produce a significant alteration o f test
controlling form ation of the enzym e pro values. In table V II are presented several
tein. E xposure to any o f the drugs listed drug interactions in diabetic hum an sub
in table V results in further m arked dere jects w hich can affect an apparent test
pression of enzym e synthesis and severe result .15
porphyria.
T he adm inistration of clofibrate to a p a
In table VI are listed several drugs in tien t taking warfarin w ill potentiate the
ducing hepatic m icrosom al enzym es .5 anticoagulant effect of w arfarin by dis
T hese enzym es can m etabolize th e drug placing it from its protein bind ing site .7
as w ell as other substrates. Barbiturates, T his interaction w ill cause a significant
griseofulvin and glutethim ide induce en increase in the prothrom bin tim e test
zymes w hich m etabolize coum arin and used to regulate w arfarin adm inistration.
p h enindion e derivatives and thus reduce D isplacem ent o f drugs from th eir b inding
th eir anticoagulant activity. D iphenylhy- sites is a com m on m echanism by w hich
dantoin and phenylbutazone stim ulate drug-drug interactions result in unex
cortisol hydroxylase activity and increase p ected laboratory data. After absorption,
the urinary excretion of B-hydroxy cor- about 50 to 80 percent of salicylate is
bound to serum album in, from w hich it
T ABLE V
d isp laces o th e r su b stan ces such as
Drugs Inducing Marked
bilirubin
and thyroxine. O ther drugs such
De-repression of Enzyme Synthesis
as coum arin may also be displaced w ith a
sudden change in prothrom bin tim e.
Chloroquine
Diallybarbiturate
Aminopyrine
Allylisopropylacetylurea
D rug-drug interactions m ay also cause
Sulfonamides
Hexachlorobenzene
enzym e induction. Ethchlorvynol, glu-
268
Drug Interaction
Hypoglycemic Drug
Alcohol
Insulin
Sulfonylurea
Phenformin
Chlorpropamide
Insulin
Insulin
Insulin
Insulin
Alcohol
Bishydroxycoumarin
Guanethidine
Oxytetracycline
Phenothiazine
Propranolol
Reaction
Inhibition of gluconeogenesis
Lactic acidosis
Decrease in excretion or metabolism of hypoglycemic agent
Decrease in insulin dosage needed to control patient
Decrease in insulin dosage needed to control patient
Increase in insulin dosage needed to control subject
Decrease in insulin dosage needed to control subject
DRUG:
10/23/75
086-24-095
ROBERT STAR
4102
GUTHRIE
HEPARIN
BLOOD
CLOTTING TIME INC
CONCENTRATION RELATED EFFECT
(WHOLE)
PHYSIOLOGICAL EFFECT
REF:
0704
BLOOD
(WHOLE)
PHYSIOLOGICAL EFFECT
REF:
0384
FACTOR V DEC
BLOOD
CONCENTRATION RELATED EFFECT
(WHOLE)
PHYSIOLOGICAL EFFECT
REF:
0384
BLOOD
FACTOR XI DEC
CONCENTRATION RELATED EFFECT
(WHOLE)
PHYSIOLOGICAL EFFECT
REF : 0384
PHYSIOLOGICAL EFFECT
REF:
0656
PITT INC
BLOOD
CONCENTRATION RELATED EFFECT
(WHOLE)
PHYSIOLOGICAL EFFECT
REF : 0704
PHYSIOLOGICAL EFFECT
REF:
0704
PHYSIOLOGICAL EFFECT
REF : 0384
FACTOR IX DEC
REPORTED EFFECT
269
(WHOLE)
AMMONIA INC
PLASMA
CONTAINS VARIABLE AMOUNTS OF AMMONIUM SALTS
ANALYTICAL EFFECT
REF:
0181
CORTICOSTEROIDS INC
PLASMA
IF CONTAMINATED BY IMPURITIES
ANALYTICAL EFFECT
REF:
0524
INSULIN DEC
PLASMA
EFFECT IN HEPARINIZED PLASMA AND SERUM
ANALYTICAL EFFECT
REF:
0709
INSULIN INC
PLASMA
SPURIOUSLY HIGH VALUES REPORTED FOR IMMUNOASSAY
ANALYTICAL EFFECT
REF : 0064
PHYSIOLOGICAL EFFECT
REF : 0704
TSH DEC
PLASMA
INTERFERES WITH THYROXINE BINDING TO PROTEIN
PHYSIOLOGICAL EFFECT
REF:
0502
270
15.
16.
17.
18.
271