Original Article Ann Clin Biochem 2001; 38: 376±385

Drug interference in clinical chemistry: recommendation of drugs

and their concentrations to be used in drug interference studies
O Sonntag1 and A Scholer 2
From the 1Scienti®c Department, Ortho-Clinical Diagnostics, c/o Schulstr. 32, D-82223 Eichenau,
Germany and the 2Kantonspital Basel, UniversitaÈtskliniken, Chemistry Laboratory, Department
Zentrallaboratorium, Petersgraben, Basel, Switzerland

SUMMARY. A group of international experts prepared two lists of drugs with their
serum/plasma and urine concentrations, which should be used when evaluating the
performance of a new laboratory method. The two lists were veri®ed by running in
vitro interference studies in three European laboratories on Hitachi instruments. The
study identi®ed the following new interferants: acid phosphatase in serum by
ibuprofen and theophylline; non-prostatic acid phosphatase in serum by cefoxitin
and doxycycline; creatine kinase MB in serum by doxycycline; total bilirubin in
serum (Jendrassik±Grof method) by rifampicin and intralipid; total bilirubin in
serum (DPD method) by intralipid; creatinine in serum (Jaffe method) by cefoxitin;
fructosamine in serum by levodopa and methyldopa; uric acid in serum by levodopa,
methyldopa and tetracycline; carbamazepine in serum by doxycycline, levodopa,
methyldopa and metronidazole; digitoxin in serum by rifampcin; phenytoin in serum
by doxycycline, ibuprofen, metronidazole and theophylline; theophylline in serum by
acetaminophen, cefoxitin, doxycycline, levodopa, phenylbutazone and rifampicin;
tobramycin in serum by cefoxitin, doxycycline, levodopa, rifampicin and
phenylbutazone; valproic acid in serum by phenylbutazone; C3 in serum by intra-
lipid; C4 in serum by doxycycline; rheumatoid factor in serum by ibuprofen and
metronidazole; pancreatic amylase and total amylase in urine by acetylcysteine,
ascorbic acid, cefoxitin, gentamicin, levodopa, methyldopa and o¯oxacin;
magnesium in urine by acetylcysteine, gentamicin and methyldopa; b2-microglobulin
in urine by ascorbic acid; total protein in urine by ascorbic acid, Ca-dobesilate and
phenylbutazone.
Interference in acid phosphatase, creatine kinase MB and bilirubin methods was
observed at very low analyte concentrations, and therefore it may not be evident at
higher concentrations. The study con®rmed the usefulness of the recommendation.

INTRODUCTION diagnostic industry if it is to provide a

Drug interference studies are a necessary and
integral part of method and instrument
evaluation. Many hundreds of drugs are in
clinical use; their blood and urine concentra-
tions vary according to their clinical use and
to pathological and physiological conditions.
This presents a formidable problem to the
Dedicated to Wolfgang Bablok to recognize his valuable
contributions in statistical methods in clinical chemistry.
W Bablok died before this publication was ®nished.
Correspondence: Dipl Chem Ing O Sonntag.
E-mail: osonntag@ocdde.jnj.com
systematic and clinically useful list of those
drugs that interfere with laboratory tests. In
1978 an expert group was convened within the
European Community to study drug interfer-
ences and establish recommendations.1 In 1984
the French Society of Clinical Chemistry and
the International Federation of Clinical Chem-
istry also addressed this issue and published, in
French and in English, recommendations for
the evaluation of drug interferences.2,3 The
National Committee for Laboratory Standards
published proposed guidelines for interference
testing in 1986.4

376
 Drug interference in clinical chemistry 377

In 1995, under the chairmanship of J Breuer METHOD

(Marienhospital, Gelsenkirchen, Germany) and
with the support of Roche Diagnostics, a group
of 18 international experts was formed to
provide advice to the diagnostic industry and
to others evaluating new methods and instru-
ments. The group was charged with preparing a
list of drugs with their serum/plasma and urine
concentrations, which should be used when
evaluating the performance of new clinical
laboratory methods. The preliminary recom-
mendations of the group were published in
1996.5 In order to verify these recommendations,
in vitro interference studies were then performed
in three European laboratories. The results of
these studies and the recommendations of the
expert group are the subject of this paper.
Part I: List of drugs recommended for
interference studied
Each expert provided a list of candidate drugs
for interference testing. From a list of 101 drugs
the experts identi®ed 18 in serum (see Table 1)
and 13 in urine (see Table 2) which were likely to
present frequent, clinically signi®cant interfer-
ence. This exercise drew support from Swedish6,7
French,8,9 English10 and American11 databases,
and from other published reports.12±18 From a
review of the literature, the group identi®ed
toxic and therapeutic concentrations for each of
the 24 drugs.6,17,19±32
Inclusion criteria used to select drugs for the
in vitro study were:

TABLE 1. Recommended drug list for in vitro drug interference studies for clinical chemical methods using serum or
plasma as sample

Concentration found in literature

Test concen- Test concen-
Active agents soluble in tration C1 tration C2 Peak Therapeutic Toxic
blank serum or plasma Clinical use (mg/L) (mg/L) (mg/L) (mg/L) (mg/L)

Acetaminophen1 Analgesic 200 20 50 10±20 150±300

Acetylcysteine Mucolytic agent 150 30 33
Acetylsalicylic acid Analgesic 1000 300 300 150±300 300±500
Ampicillin-Na Antibiotic 1000 200 2±20 >320
Ascorbic acid Vitamin 300 30 18 4±15
Ca-dobesilate Vaso- 200 20 400 6±18
therapeutic
Cefoxitin Antibiotic 2500 250 2230 up to 150
Cyclosporine Immuno- 5 1 4 >0´05±0´6 >0´62
suppressant
Doxycycline Chemotherapeutic 50 10 9
Heparin3 Anticoagulant 5000 U 10 U 0´5±1 >400
Ibuprofen1 Analgesic 500 50 50 10±30 >200
Intralipid4 Supplement 10 000 2000
Levodopa Antiparkinson’s 20 4 18 >105 >2005
agent
Methyldopa Anti- 20 4 7 up to 2 >9
hypertonic
Metronidazole Chemotherapeutic 200 10 2±5 200
Phenyl- Analgesic 400 100 120 50±110 200±400
butazone
Rifampicin Chemotherapeutic 60 20 4±10 >10
Theophylline1 Bronchodilator, 100 10 10±20 20±80
pulmonary
vasodilator
1
For these substances a separate reference serum is necessary: 100 mL ethanol (70%) + 9´9 mL of agent free serum/
plasma
2
Depends on individuals, drug interactions and other in¯uences
3
Liquemin Na (Hoffmann-La Roche) 5000 IE (=5000 U) 0´5 mL
4
For Intralipid a separate reference serum is necessary: 9´5 mL serum pool+0´5 mL NaCl (0´9%)
5
Information received after establishment of the recommendation.

Ann Clin Biochem 2001: 38

378 Sonntag and Scholer

TABLE 2. Recommended drug list for in vitro drug interference studies for clinical chemical methods using urine as
sample

Concentration found
Test concen- Test concen- in literature
Active agents soluble in tration C1 tration C2
blank serum or plasma Clinical use (mg/L) (mg/L) Peak (mg/L) Toxic (mg/L)

Acetaminophen Analgesic 3000 500 140±830

Acetylcysteine Mucolytic 10 1
Salicyluric acid1 Analgesic 6000 100 19±1350
Ascorbic acid Vitamin 4000 400 4000
Ca-dobesilate Vasotherapeutic 1000 200 1000
Na2 -cefoxitin Antibiotic 12 000 2000 24 000 3000
Gentamicin sulphate Antibiotic 400 80 16±125
Ibuprofen Analgesic 4000 500 1000
Levodopa Antiparkinson’s agent 1000 250
Methyldopa Antibiotic 2000 200 1400
O¯oxacin Analgesic 900 100 250±350
Phenazopyridine Antibiotic 300 50
Tetracycline Antibiotic 300 100
1
Metabolite of 4-aminosalicylic acid and salicylic acid.

. Known interferent Part II: Veri®cation experiment

. Frequent clinical use Procedure
. Clinical relevance The study covered two phases: a screen for
. Absorbs light at a wavelength close to that effects at elevated drug levels (C1) and a
used for test measurement validation phase to check for interference at
more clinically relevant levels (C2).

For the urine studies, if metabolites are 1. Screening (C1)

excreted in place of the parent drug the
major metabolite should be used; however,
this is subject to the availability of the
metabolite.
Two different concentrations of each drug
were adopted. To reveal potential interference in
in vitro screening a very high drug concentration
(C1) was used. C1 represents a typical toxic
concentration, and where interference was
identi®ed a validation experiment was per-
formed using a therapeutic drug concentration
(C2).
Two tables were prepared, one for blood (see
Table 1) and the other for urine (see Table 2).
These include the international non-proprietary
name (INN) of the drug, its clinical use, drug
concentrations C1 and C2, and the highest blood
and urine drug found in the literature. Thera-
peutic peak and toxic concentrations have been
included where they are available.
When studying drug interference the analyte
concentration used should be close to a clinical
decision level, perhaps the upper or lower
normal reference limit. This recommendation
was adopted in the validation experiment.
In the screening experiment ®ve replicates of a
drug-free pool were analysed, followed by
analysis of ®ve replicates of a pool containing
the drug under investigation. A simple auto-
matic wash step as typically programmed in the
instrument was performed between each sample
to minimize sample carry-over.
2. Validation (C2)
In the validation experiment, analysis of 10
replicates of the drug-free pool was followed by
analysis of 10 replicates of the spiked drug pool,
with a wash step between each sample.
Material
The methods used in these studies (see Tables 3
and 4) were all performed on Hitachi 917
analysers (Roche Diagnostics, Mannheim,
Germany). In both experiments the analytical
system was calibrated and quality controlled
according to the recommendations of the
manufacturer. For each analyte a drug-free pool
of serum or urine was collected by the three
laboratories (Kantonsspital, Basel, Switzerland;
Hospital Germans Trias i Pujol, Barcelona,

Ann Clin Biochem 2001: 38

 Drug interference in clinical chemistry 379

TABLE 3. Analytes and methods used for interference studies and observed drug interference in serum

Inter-
Activity or ference Inter- Observed
concen- Analyte limit ference deviation
Analyte Method ID no. tration unit (%) caused by (%)

Enzymes, 378C
Acid phosphatase PNP 1553437 1´1 U/L +30 Ibuprofen +76 n
Theophylline +57 n
Acid phosphatase, PNP, 1553437 1´6 U/L +30 Cefoxitin +34 n
non-prostatic tartrate Doxycycline +69 n
Alanine amino- IFCC, 1876805 19 U/L +20
transferase P-5-P
Alkaline DEA, 1662961 160 U/L +20
phosphatase DGKC*
Alkaline AMP, 1557033 72 U/L +20
phosphatase IFCC*
Amylase, EPS* 1491326 62 U/L +20
pancreatic
Amylase, EPS 1729322 28 U/L +20
pancreatic (liquid)*
Amylase, total EPS* 1491300 133 U/L +20
Amylase, total EPS (liquid)* 1729314 59 U/L +20
Aspartate IFCC, 1876848 23 U/L +20
aminotransferase P-5-P*
Cholinesterase Butyryl 1551329 9833 U/L +20
thiocholine*
Creatine kinase NAC 1552147 148 U/L +20
Creatine kinase NAC, 1127608 7 U/L +20 Doxycycline +28 n
MB immunological
Glutamate DGKC 1442422 2´5 U/L +20
dehydrogenase
g-Glutamyl IFCC 1730053 24 U/L +20
transpeptidase
g-Glutamyl Szasz 1551906 20 U/L +20
transpeptidase
a-Hydroxy DGKC* 1552350 108 U/L +20
butyrate
dehydrogenase
Lactate IFCC 1552384 250 U/L +20
dehydrogenase (liquid)*
Lactate SFBC* 1442635 365 U/L +20
dehydrogenase
Lipase Turbidimetric* 1491237 86 U/L +20

Substrates, ions and proteins

Albumin Bromcresol 1127448 4´93 g/dL +10
green*
Ammonia GlDH 125857 215 g/dL +15
Bicarbonate enzymatic, UV 102050 25 mmol/L +15
Bilirubin, total Jendrassik± 123927 0´62 mg/dL +10 Rifampicin +13 n
Grof Intralipid +22 n
Bilirubin, total DPD 1552414 0´56 mg/dL +10 Intralipid 742 n
Calcium o-Cresolph- 1551272 2´24 mmol/L +5
thaleine
Chloride ISE diluted 1298097 108 mmol/L +5
Cholesterol, PAP 1661426 49 mg/dL +10
HDL (direct)
Cholesterol, total PAP 1491458 191 mg/dL +10
Creatinine Jaffe 1551876 0´93 mg/dL +10 Cefoxitin +18 n

continued

Ann Clin Biochem 2001: 38

380 Sonntag and Scholer

TABLE 3. continued

Inter-
Activity or ference Inter- Observed
concen- Analyte limit ference deviation
Analyte Method ID no. tration unit (%) caused by (%)

Creatinine PAP 1551841 0´71 mg/dL +10 Ca-dobesilate 745 k

Levodopa 717 k
Creatinine Enzymatic HTB 1775685 1´21 mg/dL +10 Ca-dobesilate 712 k
Fructosamine Colorimetric 1101668 244 mmol/L +10 Levodopa +24 n
Methyldopa +16 n
Glucose GOD-PAP* 1491253 81 mg/dL +10
Glucose Hexokinase 1491199 89 mg/dL +10
Iron Ferrozine 1490869 93 mg/dL +5
Lactate Enzymatic, UV 256773 3´0 mmol/L +10
Magnesium Xylidylic blue 1551353 0´77 mmol/L +5
Phosphorus Molybdate 1551388 1´03 mmol/L +5
Potassium ISE diluted 0825441 3´43 mmol/L +5
Protein, total Biuret 1551418 7´0 g/dL +10
Sodium ISE diluted 0825468 200 mmol/L +5
Triglycerides GPO PAP 1730711 113 mg/dL +10 Ca-dobesilate 713 k
Urea Urease/GIDH 1729691 37 mg/dL +10
Uric acid Uricase PAP 1662759 5´3 mg/dL +10 Levodopa 737 n
Methyldopa 721 n
Tetracycline 722 n

TDM and hormones

Carbamazepine CEDIA 1447416 24´7 mg/L +15 Doxycycline +19 n
Levodopa +19 n
Methyldopa +37 n
Metronidazole +17 n
Digitoxin CEDIA 129905 21´6 nmol/L +15 Rifampicin 720 n
Digoxin TINA 1447726 6´0 nmol/L +15
Gentamicin CEDIA* 1299948 22´8 mg/L +15
Phenobarbital CEDIA 1299930 89´2 mg/L +15
Phenytoin CEDIA 1299921 15´7 mg/L +15 Doxycycline +63 n
Ibuprofen +49 n
Metronidazole +28 n
Theophylline +95 n
T uptake CEDIA 1179675 35´9 % uptake +15
T4 CEDIA* 1179667 7´2 mg/L +15
Theophylline CEDIA 1299883 33 mgL +15 Acetaminophen +64 n
Cefoxitin +24 n
Doxycycline +39 n
Levodopa +65 n
Phenylbutazone +59 n
Rifampicin +65 n
Tobramycin CEDIA 1299956 13´9 mg/L +15 Cefoxitin +24 n
Doxycycline +39 n
Levodopa +65 n
Rifampicin +39 n
Phenylbutazone +59 n
Valproic acid CEDIA 1488589 146´2 mg/L +15 Phenylbutazone +27 n

Speci®c proteins
a1-acid glycoproteinTINA* 1557602 1´27 g/L +10
a1-microglobulin TINA* 1203622 40´8 mg/L +10
b2-microglobulin TINA* 1660551 5´65 mg/L +10
Apolipoprotein A-1TINA* 1551680 1´55 g/L +10
Apolipoprotein B TINA* 1551779 1´21 g/L +10

continued

Ann Clin Biochem 2001: 38

 Drug interference in clinical chemistry 381

TABLE 3. continued

Inter-
Activity or ference Inter- Observed
concen- Analyte limit ference deviation
Analyte Method ID no. tration unit (%) caused by (%)

ASLO TINA* 1552228 116´4 lU/mL +10

C3 TINA 852597 1´83 g/L +10 Intralipid +31 n
C4 TINA 852619 0.39 g/L +10 Doxycycline +13 n
C-reactive protein TINA* 1551922 22.5 mg/L +10
Ferritin TINA* 1661400 501 mg/L +10
IgA TINA* 1552325 2.92 g/L +10
IgG TINA* 1552252 10.4 g/L +10
IgM TINA* 1552295 2.06 g/L +10
Albumin TINA 1203622 170.4 g/L +10
Myoglobin TINA 1660560 88.9 mg/L +10
Pre-albumin TINA* 1660519 0.30 g/L +10
Rheumatoid factor TINA 1552007 9.83 IU/mL +10 Ibuprofen +12 n
Metronidazole +19 n
Transferrin TINA* 1552180 32.0 mmol/L +10

*=No interference founded for this method in this study (neither with C1 nor C2); n=new interference; k=known
interference; ID no.=identi®cation number.

Spain; and UniversitaÁ Degli Studi di Milano,
Desio, Italy). The drug-free pools were prepared
from donors taking no drugs. Spiked drug pools
were prepared from either the parent drug or its
metabolite. Ethanol was used as a solvent for
those drugs that were insoluble in water. The
pools prepared for studying therapeutic drugs or
drugs of abuse were spiked with the parent drug
(Sigma, Buchs, Switzerland). These drugs were:
Drugs of abuse
D,L-amphetamine sulphate, Na-barbiturate, D-
lysergic acid diethylamide, propoxyphene-HCl
and phencyclidine-HCl.
Therapeutic drugs
Digitoxin (Fluka, Buchs, Switzerland), digoxin,
gentamicin, phenobarbital, phenytoin, theophyl-
lin, tobramycine, valproic acid.
Statistics
Data were subject to statistical analysis using
Computer-Aided Evaluation software (Roche,
Mannheim, Germany) developed by Bablok
et al.33
Interpretation
A clinically acceptable degree of interference,
termed interference limit, was agreed by the
expert group for each analyte studied and is
included in Tables 3 and 4. These limits were
derived from inspection of analytical perform-
ance data in German, English and French
external quality assessment schemes (EQAS).
The clinical signi®cance of these analytical limits
was reviewed and modi®ed by the group to
provide the recommendations included in Tables
3 and 4.
Drugs that showed interference in the screen-
ing experiment were included in the validation
study, and only those that then demonstrated
interference were considered to be clinically
relevant.
RESULTS
The results of the validation experiment at
clinically relevant drug concentrations are given
in Tables 3 and 4. The results of the screening
experiment using high drug concentrations (C1)
have not been included but are available on
request to the corresponding author.
The following analytes in serum showed no
interference at high (C1) and normal (C2) drug
concentrations when using the methods de-
scribed in Table 3: alkaline phosphatase,
amylase, aspartate aminotransferase, cholines-
terase, b-hydroxy butyrate dehydrogenase,
lactate dehydrogenase, albumin, glucose, total
protein, gentamicin, thyroxine (T4), a1-acid
glycoprotein, a1-microglobulin, b2-microglobu-
lin, apolipoprotein A1, apolipoprotein B, anti-
streptolysin-O, C-reactive protein, ferritin, IgA,
IgG, IgM, prealbumin, transferrin; and in
Table 4 in urine for amphetamines, cannabi-
noids, methadone, opiates and propoxyphene.

Ann Clin Biochem 2001: 38

382 Sonntag and Scholer

TABLE 4. Analytes and methods used for interference studies and observed drug interference in urine

Activity or Observed
concentra- Analyte Interference Interference deviation
Analyte Method ID no. tion unit limit (%) caused by (%)

Enzymes, 378C
Amylase, EPS 1491326 325 U/L +20 Acetylcysteine +27 n
pancreatic Ascorbic acid +28 k
Cefoxitin +23 n
Gentamicin +28 n
Levodopa +26 n
Methyldopa +34 n
O¯oxacin +37 n
Amylase, EPS 1729322 139 U/L +20 Acetylcysteine +26 n
pancreatic (liquid) Ascorbic acid +26 k
Cefoxitin +22 n
Gentamicin +27 n
Levodopa +24 n
Methyldopa +32 n
O¯oxacin +35 n
Amylase, total EPS 1491300 436 U/L +20 Acetylcysteine +25 n
Ascorbic acid +26 k
Cefoxitin +24 n
Gentamicin +25 n
Levodopa +23 n
Methyldopa +30 n
O¯oxacin +33 n
Amylase, EPS 1729314 199 U/L +20 Acetylcysteine +25 n
total (liquid) Ascorbic acid +26 k
Cefoxitin +26 n
Gentamicin +24 n
Levodopa +22 n
Methyldopa +30 n
O¯oxacin +32 n
Substrates and ions
Calcium o-Cresolph- 1551272 6´62 mmol/L +5
thaleine
Chloride ISE diluted 1298097 156 mmol/L +5
Creatinine Jaffe 1551272 163 mg/dL +10
Creatinine PAP 1551841 172 mg/dL +10
Glucose Hexokinase 1491199 9´2 mg/dL +10
Magnesium Xylidylic 1551353 4´14 mmol/L +5 Acetylcysteine +42 n
blue Gentamicin +29 n
Methyldopa +22 n
Phosphorus Molybdate 1551388 36.7 mmol/L +5
Potassium ISE diluted 1298011 80.5 mmol/L +5
Sodium ISE diluted 1298054 177 mmol/L +20
Urea Urease/GI- 1729691 2378 mg/dL +10
DH
Uric acid Uricase 1662759 59´8 mg/dL +10
PAP

DAU
Amphetamines CEDIA* 1557343 2396 ng/mL +20
quant. 1000
(cut-off)
Barbiturates CEDIA 1557351 2368 ng/mL +20
quant. 300
(cut-off)

continued

Ann Clin Biochem 2001: 38

 Drug interference in clinical chemistry 383

TABLE 4. continued

Activity or Observed
concentra- Analyte Interference Interference deviation
Analyte Method ID no. tion unit limit (%) caused by (%)

Cannabinoids CEDIA* 1557394 277 ng/mL +20

(THC) quant. 50
(cut-off)
Benzoylecgonin CEDIA 1557378 2992 ng/mL +20
(Cocaine quant. 300
metabolite) (cut-off)
LSD (Lysergic CEDIA 1732137 2´08 ng/mL +20
acid diethylamide) quant. 50
(cut-off)
Methadone CEDIA* 1730894 1008 ng/mL +20
quant. 300
(cut-off)
Opiates CEDIA* 1557386 1676 ng/mL +20
quant. 300
(cut-off)
Propoxyphene CEDIA* 1661507 855 ng/mL +20
quant. 300
(cut-off)
Phencyclidine CEDIA 1557408 252 ng/mL +20
quant. 25
(cut-off)

Speci®c proteins
b2-microglobulin TINA 1660551 3´83 mg/L +15 Ascorbic acid +46 n
Microalbumin TINA 1203622 210´5 mg/L +15
Protein, total Benzetho- 1815199 0.31 mg/L +15 Ascorbic acid +74 n
nium- Ca-dobesilate 732 n
chloride Phenylbutazone 719 n

*No interference found for this method in this study (neither with C1 nor C2). n=New interference; k=known
interference; ID no.=identi®cation number; DAU=drugs of abuse; THC=tetrahydrocannabinol;
quant.=quantitative.

Drug interference was observed in serum at
normal (C2) drug concentrations for acid
phosphatase, creatine kinase MB, total bilirubin,
creatinine, fructosamine, triglycerides, uric acid,
carbamazepine, digitoxin, phenytoin, theophyl-
line, tobramycin, valproic acid, complement 3
(C3), complement 4 (C4) and rheumatoid factor
(see Table 3).
Interference was also observed in urine at
normal (C2) drug concentrations for amylase,
magnesium, b2-microglobulin and total protein
(see Table 4).
DISCUSSION AND CONCLUSION
Most analytes showed no drug interference even
at the very high drug concentrations that might
be seen with suicidal overdoses. This should
reassure both clinical laboratories and manu-
facturers of clinical chemistry analysers.
Drug interference studies can be misleading in
some clinical situations and this is illustrated
below:
. Levodopa is metabolized into the endo-
genous substances dihydroxyphenylacetic
acid and homovanillic acid. Clearly, this
makes the use of metabolite in drug
interference studies dif®cult. Interference
can therefore be mediated either by a
pathological process producing these meta-
bolites or by drug interference.
. The metabolites of ibuprofen, (+)-2-[p-(2
hydroxymethyl-propyl) phenyl] propionic
acid and (+)-2-[p-(2 carboxy-propyl) phe-
nyl] propionic acid were not available for
this study. The use of the parent drug in
place of the metabolites cannot adequately
re¯ect physiological conditions and might
therefore be misleading.

Ann Clin Biochem 2001: 38

384 Sonntag and Scholer
The interfering potential of the drugs marked
as `known’ in Tables 3 and 4 has already been
recognized and published.1±9,11
This study identi®ed the following new
interferants: acid phosphatase in serum by
ibuprofen and theophylline; non-prostatic acid
phosphatase in serum by cefoxitin and doxy-
cycline; creatine kinase MB in serum by
doxycycline; total bilirubin in serum (Jendrassik±
Grof method) by rifampicin and intralipid; total
bilirubin in serum (DPD method) by intralipid;
creatinine in serum (Jaffe method) by cefoxitin;
fructosamine in serum by levodopa and methyl-
dopa; uric acid in serum by levodopa, methyl-
dopa and tetracycline; carbamazepine in serum
by doxycycline, levodopa, methyldopa and
metronidazole; digitoxin in serum by rifampcin;
phenytoin in serum by doxycycline, ibuprofen,
metronidazole and theophylline; theophylline in
serum by acetaminophen, cefoxitin, doxycycline,
levodopa, phenylbutazone and rifampicin;
tobramycin in serum by cefoxitin, doxycycline,
levodopa, rifampicin and phenylbutazone; val-
proic acid in serum by phenylbutazone; C3 in
serum by intralipid; C4 in serum by doxycycline;
rheumatoid factor in serum by ibuprofen and
metronidazole; pancreatic amylase and total
amylase in urine by acetylcysteine, ascorbic acid,
cefoxitin, gentamicin, levodopa, methyldopa and
o¯oxacin; magnesium in urine by acetylcysteine,
gentamicin and methyldopa; b2-microglobulin in
urine by ascorbic acid; total protein in urine by
ascorbic acid, Ca-dobesilate and phenylbuta-
zone.
Interference in acid phosphatase, creatine
kinase MB and bilirubin methods was observed
at very low analyte concentrations, and therefore
it may not be evident at higher concentrations.
In vitro studies cannot accurately re¯ect the in
vivo interference effects of drugs and their
metabolites. This study has identi®ed those
drugs that cause interference under in vitro
conditions, but cannot be considered either
de®nitive or comprehensive. Rapid develop-
ments in analytical chemistry and the introduc-
tion of new and more complex drug
preparations makes it essential that the clinical
chemist remains vigilant to the potential for
drug interference. The goal of this study was
to present a model for further interference
studies for manufacturer of diagnostic kits or
clinical chemists evaluating a new method. The
mechanism of interference was not investigated
in this study and should be further investi-
gated.
Ann Clin Biochem 2001: 38
Acknowledgement
The authors acknowledge support for this study
from Roche Diagnostics, Mannheim, Germany.
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Accepted for publication 16 March 2001
Ann Clin Biochem 2001: 38