Primer on Drug Interferences with Test Results

in Basic Skills in Interpreting Laboratory Data
Author: Mary Lee
Free access

OBJECTIVES

After completing this chapter, the reader should be able to

  • Distinguish between in vivo and in vitro drug interferences with laboratory tests

  • Identify suspected drug–laboratory test interference in a logical, systematic manner given a drug and a laboratory test

  • Devise a stepwise process to confirm that a drug is causing a clinically significant drug–laboratory test interference

  • Distinguish among tertiary, secondary, and primary literature resources about drug–laboratory test interferences

  • Apply a systematic process to search and identify medical literature relevant to a suspected drug–laboratory test interference

Through a variety of mechanisms, drugs can interfere with laboratory test results. If the clinician who has ordered the laboratory test is not aware that the drug has altered the results of the test, inappropriate management of the patient may follow, including unnecessary hospitalization, extra office visits, or additional laboratory or clinical testing—all of which may increase the cost of healthcare. This chapter addresses this situation and provides resources that health professionals can use to better interpret laboratory tests when a drug is suspected to interfere with test results.

IN VIVO AND IN VITRO DRUG INTERFERENCES WITH LABORATORY TESTS

When a drug interferes with a laboratory test result, it alters the laboratory value. Mechanisms for drug interference of clinical laboratory tests can be classified as either in vivo or in vitro.1 In vivo drug interferences can also be called physiologic and can be subclassified as pharmacological or toxicological. In vivo drug interferences account for most effects of drugs on laboratory tests.2 In contrast, the term in vitro drug interferences is used synonymously with analytical or methodological interferences.

In Vivo Interference

An in vivo interference is an actual change in the analyte concentration or activity prior to specimen collection and analysis. The assay measurement is actual and accurate and reflects a change in the measured substance that has occurred in the patient. Therefore, an in vivo interference will always change a laboratory test result, independent of the assay methodology. A drug can produce an in vivo interference in several ways. By a direct extension of its pharmacological effects, a drug can produce changes in some laboratory test results. For example, thiazide and loop diuretics will commonly cause increased renal elimination of potassium. Therefore, decreased serum potassium levels can occur in treated patients. In these patients, hypokalemia is actual and accurate. Similarly, β adrenergic antagonists decrease renin and aldosterone secretion, which can lead to increased serum potassium levels.2

Other drugs produce changes in laboratory test results by producing in vivo toxicological effects. As the drug damages a particular organ system, abnormal laboratory tests may be one of the first signs of the problem. For example, as isoniazid and rifampin produce hepatotoxicity, elevated hepatic transaminases will signal the onset of liver inflammation. Similarly, as a prolonged course of high-dose aminoglycoside antibiotic causes acute proximal tubular necrosis, serum creatinine and serum trough aminoglycoside levels will increase steadily if the antibiotic is not stopped or if the antibiotic dose is not reduced. In the face of cyclophosphamide-induced bone marrow suppression, neutropenia will become evident 10 to 14 days after a dose has been administered.

In Vitro Interference

Drugs in a patient’s body fluid or tissue can directly interfere with a clinical laboratory test during the in vitro analytical process. This type of drug–laboratory test interaction is highly dependent on the laboratory test methodology, as the reaction may occur with one specific assay method but not another. In vitro drug-laboratory test interactions are common with radioimmunoassays for which cross reactions can occur because of drug metabolites or drugs that are chemically similar to the parent drug, or because of heterophilic antibodies that are similar to endogenous antibodies. False high or false low laboratory test results occur.2-5 For example, serum digoxin levels are commonly determined using a radioimmunoassay, a fluorescent polarization immunoassay, or a TDx assay. However, these assays are based on the three-dimensional structure of the digoxin molecule, and many other drugs with a similar chemical structure to digoxin (eg, spironolactone, estrogen replacement products, cortisol, digoxin metabolites) can cross-react with the assay.6 A falsely increased or decreased serum digoxin level can result. To determine the true serum digoxin level in this situation, another assay technique (eg, high-pressure liquid chromatography [HPLC]) may be used. In addition, substances that are prepackaged in or added to the in vitro system before or after sample collection can cause laboratory test interference in vitro. As an example, test tubes sometimes contain lithium heparin or sodium fluoride. Heparin can interfere with aminoglycoside assays, and fluoride can cause false increases in blood urea nitrogen (BUN) when measured by the Ekatchem assay.

Alternatively, a drug may cause discoloration of the body fluid specimen, which may interfere with colorimetric, photometric, or fluorometric laboratory-based assay methods. For example, phenazopyridine causes an orange-red discoloration of urine that may be mistaken for blood. Nitrofurantoin may cause a brown discoloration of the urine that may alarm the patient. These types of drug interference with laboratory testing can be detected visually and appropriate attribution of the abnormality should be made by knowledgeable clinicians and clinical laboratory staff.

Other common mechanisms by which drugs cause in vitro interferences with laboratory tests include the following:

  • A drug alters the specimen pH (usually urine) so that reagent reactions are inhibited or enhanced. For example, acetazolamide produces an alkaline urinary pH that causes false-positive proteinuria with reagent dip strips.

  • A drug chelates with an enzyme activator or reagent used in the in vitro laboratory analysis. For example, large doses of biotin, as are included in some over-the-counter nutritional supplements, can compete for the biotin-streptavidin complex which is a component of many radioimmunoassays.3,7-9 Also, daptomycin interacts with rabbit or human thromboplastin, which is associated with a dose-dependent prolongation of prothrombin time and international normalized ratio.10,11

  • A drug absorbs at the same wavelength as the analyte. For example, methotrexate interferes with analytic methods using high performance liquid chromatography and an absorbance range of 340 to 410 nm.

  • A drug reacts with reagent to form a chromophore (eg, cefoxitin or cephalothin) with the Jaffe-based creatinine assay.

In addition to the parent drug, other drug-related components may cause significant interferences with laboratory tests. Metabolites can cross-react with the parent drug in an assay, such as in the case with cyclosporine. Its metabolites cross-react with the parent drug in HPLC assays and can produce a falsely high measurement of the concentration of cyclosporine.12 Contaminants in herbal products, which are subject to less regulation than medications in the United States, may interfere with some laboratory tests.7 Inactive ingredients of some drug products, which includes excipients such as lactose or starch, preservatives, colorants, or flavoring agents, may influence assay results. Although most manufacturers do report the inactive ingredients in their products, little systematic research has been performed to assess the impact of these substances on laboratory tests. Compounding these factors, many laboratory test interferences are concentration related, and many drug metabolites and their usual plasma concentrations have yet to be identified. Therefore, systematic study of all of these potential causes of interactions is difficult to conduct and is not available in many cases.13

Simultaneous In Vivo and In Vitro Effects

Some drugs can affect an analyte both in vivo and in vitro. In these situations, interpretation is extremely difficult because the degree of impact in each setting cannot be determined easily. For example, when a drug produces hemolysis in a patient with glucose-6-phosphate dehydrogenase deficiency who is exposed inadvertently to ciprofloxacin, hemolytic anemia may result. Hemolyzed red blood cells produce a red discoloration of the plasma or serum. The hemoglobin released from the damaged red blood cells can interfere with analysis of alkaline phosphatase or γ-glutamyl transferase, both of which can be assayed using a spectrophotometric analysis that depends on color changes after a chemical reaction.13,14 Simultaneous in vivo and in vitro drug interferences with laboratory tests can also occur commonly when drugs increase bilirubin or when a drug causes lipemia.15

IDENTIFYING DRUG INTERFERENCES

Incidence of Drug Interferences

The true incidence of drug interferences with laboratory tests is unknown. This is because many situations probably go undetected. However, as the number of laboratory tests and drugs on the U.S. commercial market increase, it is likely that the number of cases of in vivo interferences will also increase. As a reflection of this, consider the number of drug–laboratory test interferences reported by D. S. Young, author of one of the classic literature references on this topic. In the first edition of Effects of Drugs on Clinical Laboratory Tests, published in the journal Clinical Chemistry in 1972, 9,000 such interactions were included.16 In the second edition of the same publication, which was published in 1975, 16,000 such interactions were reported.17 In 1997, this resource, which had been converted to an online searchable database, included more than 135,000 interactions.18 In 2014, this resource included 171,000 interactions.19

As for in vitro interferences, the number of drug–laboratory test interferences may be moderated over time because of newer, more specific laboratory test methodologies that minimize cross-reactions with drug metabolites or drug effects on reagents or laboratory reactions.14,18 In addition, manufacturers of commonly used laboratory equipment systematically study the effects of drugs on assay methods.17 Therefore, this information is often available to clinicians who confront problematic laboratory test results in patients. This increased awareness reduces the number of patients who are believed to have experienced newly reported drug–laboratory test interferences.

Suspecting a Drug Interference

A clinician should suspect a drug–laboratory test interference when an inconsistency appears among related test results or between test results and the clinical picture. Specifically, clinicians should become suspicious when the following occurs:

  • Test results do not correlate with the patient’s signs, symptoms, or medical history.

  • Results of different tests—assessing the same organ anatomy or organ function, or the drug’s pharmacologic effects—conflict with each other.

  • Results from a series of the same test vary greatly over a short period of time and for no apparent reason.

  • Serial test results are inconsistent.

No Correlation with Patient’s Signs, Symptoms, or Medical History

As emphasized elsewhere in this book, when an isolated test result does not correlate with signs, symptoms, or medical history of the patient, the signs and symptoms should be considered more strongly than the test result. This rule is particularly true when the test result is used to confirm suspicions raised by the signs and symptoms in the first place or when the test result is used as a surrogate marker or indirect indicator of underlying pathology.

For example, serum creatinine is used in various formulae to approximate the glomerular filtration rate, which is used to assess the kidney’s ability to make urine. However, actual urine output and measurement of urinary creatinine excretion is a more accurate method of assessing overall renal function. If a patient’s serum creatinine has increased from a baseline of 1 mg/dL to 5 mg/dL over a three-day period, but the patient has had no change in urine output, urinary creatinine excretion, or serum electrolyte levels, then the serum creatinine level may be elevated because of a drug interference with the laboratory test. Similarly, if a patient has a total serum bilirubin of 6 mg/dL, but the patient is not jaundiced or does not have scleral icterus, then a drug interference with the laboratory test should be considered.

Conflicting Test Results

Occasionally, pharmacological or toxicological effects of a drug produce conflicting results of two tests that assess the same organ function. For example, a presurgical test screen shows a serum creatinine of 4.2 mg/dL in an otherwise healthy 20-year-old patient with a BUN of 8 mg/dL. Usually, if a patient had true renal impairment, BUN and serum creatinine would be elevated in tandem. Thus, in this patient, a drug interference with the laboratory test is suspected. Further investigation revealed that the patient received cefoxitin shortly before blood was drawn for the laboratory test. Cefoxitin can falsely elevate serum creatinine concentrations. Thus, the elevated serum creatinine is likely due to drug interference with the laboratory test and not to renal failure. To confirm that this is the case, cefoxitin should be discontinued and the serum creatinine repeated after that. If it is due to the drug, the elevated serum creatinine should return to the normal range.20

Varying Serial Test Results Over a Short Time Period

Typically, the results of a specific laboratory test should follow a trend in a patient. However, in the absence of a new onset of medical illness or worsening of existing disease, a sudden change in the laboratory test result trend should cause examination of a possible drug interference with a laboratory test. For example, prostate specific antigen (PSA) is a tumor marker for prostate cancer. It is produced by glandular epithelial cells of the prostate. The normal serum level is <4 ng/mL in a patient without prostate cancer, and the level is typically elevated in patients with prostate cancer. However, it is not specific for prostate cancer. Elevated PSA serum levels are also observed in patients with benign prostatic hyperplasia, prostatitis, or following instrumentation of the prostate. A 70-year-old male patient with metastatic prostate cancer has a PSA of 30 ng/mL and has decided not to undergo treatment. Four serial PSA tests over the course of one year and done at three-month intervals show no change. Despite the absence of any changes on pelvic computerized axial tomography, bone scan, or chest radiograph, his PSA is 10 ng/mL at his most recent office visit. After a careful interview of the patient, the urologist discovers that the patient has been treated for androgenetic alopecia for the past six months with finasteride. The patient received the prescription from another physician for lower urinary tract voiding symptoms, and finasteride lowered the PSA level.21

Serial Test Results That Are Inconsistent with Expected Results

Generally, repeated laboratory test results should show little change over time assuming that the status of the medical condition or treatment for the medical condition in an individual patient stays the same. However, when serial test results are inconsistent with expected results, a drug–laboratory test interference should be suspected. For example, leuprolide, a luteinizing hormone-releasing hormone (LHRH) agonist, is useful in the management of prostate cancer, which is an androgen dependent tumor. Persistent use of leuprolide causes down-regulation of pituitary LHRH receptors, decreased secretion of luteinizing hormone, and decreased production of testicular androgens. A patient with prostate cancer treated with leuprolide should experience a sustained reduction in serum testosterone levels from normal (280 to 1,100 ng/dL) to castration levels (<50 ng/dL) after 2 to 3 weeks. The serum testosterone level should remain below 50 ng/dL as long as the patient continues treatment with leuprolide, and as long as he makes returns to the clinic for repeated doses on schedule. However, one of the adverse effects of leuprolide is decreased libido and erectile dysfunction, which is a direct extension of the drug’s testosterone-lowering effect. Such a patient may seek medical treatment of sexual dysfunction, and he may be inappropriately prescribed depot testosterone injections. Thus, in this case, depot testosterone injections will cause a change in serum testosterone levels in the wrong direction. If serum testosterone levels increase, this should be a signal that the patient has serial test results, which are inconsistent with expected results of leuprolide, and an investigation should be done as to the cause (Minicase 1).22

How can a vitamin cause any problems?

Annie J., a 30-year-old female patient, developed multiple sclerosis and began taking a biotin nutritional supplement in a dose of 300 mg by mouth daily. The patient has heard that biotin can slow disease progression. Two months later, during an annual physical examination, a full set of clinical laboratory tests was obtained that showed significantly elevated serum free thyroxine (FT4), elevated free triiodothyronine (FT3), and low thyroid stimulating hormone (TSH). Upon reviewing these laboratory test results, the physician scheduled the patient for a follow-up clinic visit. A physical examination showed a normal size thyroid gland with no nodules on palpation, a normal heart rate, no tachycardia, and normal blood pressure. The patient did not have exophthalmos. In review of systems, the patient had no reports of weight loss, palpitations, hyperactivity, nervousness, or mood swings. A medication history showed that the only new medication started prior to the blood drawing was biotin. Because the efficacy of biotin for multiple sclerosis has not been proven, the physician asked the patient to discontinue biotin and to have thyroid function tests repeated in 1 week.

QUESTION: Assume that biotin caused a drug-laboratory test interference. Was the interference an in vitro or an in vivo interference? What is the mechanism by which biotin most likely caused the interference?

DISCUSSION: Biotin causes an in vitro drug-laboratory test interaction with thyroid function tests. FT4, FT3, and TSH testing are commonly performed by radioimmunoassay, which employs a streptavidin-biotin complex. Exogenous biotin in the patient’s blood sample, which resulted from oral administration of biotin, interfered with the streptavidin-biotin complex’s binding with thyroid hormones and led to false assay measurements.3,7-9

Although the patient’s FT4 and FT3 suggest that patient has hyperthyroidism, the patient has no symptoms consistent with the disease. Moreover, the onset of the abnormal laboratory tests appears to be temporally related to the start of biotin, and normalization of thyroid function tests should occur after biotin is discontinued. These all suggest that the patient has a biotin-induced laboratory test interference.

MANAGING DRUG INTERFERENCES

When a drug is suspected to interfere with a laboratory test, the clinician should collect appropriate evidence to confirm the interaction by taking the following steps:

  1. Establishing a temporal relationship between the change in the laboratory test and drug use and ensuring that the change in the laboratory test occurred after the drug was started or after the drug dose was changed

  2. Ruling out other drugs as causes of the laboratory test change

  3. Ruling out concurrent diseases as causes of the laboratory test change

  4. If possible, discontinuing the causative agent and repeating the test to see if dechallenge results in a correction of the abnormal laboratory test

  5. Choosing another laboratory test that will provide assessment of the same organ’s function, but is unlikely to be affected by the drug (the clinician can compare the new results against the original laboratory test result, and check for dissimilarity or similarity of results)

  6. Finding evidence in the medical literature that documents the suspected drug–laboratory test interference

  7. Contacting the head of diagnostic labs who maintains or has access to computerized lists of drugs that interfere with laboratory tests (the person would also provide assistance in interpreting aberrant laboratory test results)13

For any particular patient case, it is often not possible to obtain information on all seven of the previously listed items. The first four items are crucial in any suspected drug–laboratory test interference. With the availability of highly accessible, electronic databases—which can scour the literature quickly for drug–laboratory test interactions—and more electronic cross-talk between databases for clinical laboratory tests and those for medications, clinicians can easily find published information about drug interferences with laboratory tests; consult with a clinical laboratory specialist, if necessary, and then take the appropriate steps in managing the patient (Minicase 2).23,24

LITERATURE RESOURCES

A systematic search of the medical literature is essential for providing the appropriate evidence to confirm the drug–laboratory test interaction. This search will ensure that a complete and comprehensive review—necessary in making an accurate assessment—has been done. When searching the literature, it is recommended to use the method originally described by Watanabe et al and, subsequently, modified by C. F. Kirkwood.25,26 Using this technique, the clinician would search tertiary, secondary, and then primary literature. Although there are slight variations in the types of publications included in each category, a brief description of each literature category follows.

Trimethoprim–Sulfamethoxazole-Induced Hypoprothrombinemia

Sally S., a 65-year-old female patient, is started on trimethoprim–sulfamethoxazole 800/160 mg by mouth twice daily for an upper urinary tract infection due to Escherichia coli. Antibiotic treatment will continue for 14 days. She has atrial fibrillation and is also taking digoxin 0.125 mg by mouth daily and warfarin 2.5 mg by mouth daily. She has been on warfarin for years and says that she is fully aware of all the DOs and DON’Ts of taking warfarin. Her International Normalized Ratio (INR) regularly and consistently is 2.5, which is therapeutic. She has no history of liver disease and appears healthy and well nourished. Prior to the start of the trimethoprim-sulfamethoxazole, her serum sodium was 137 mEq/L, potassium 4 mEq/L, BUN 10 mg/dL, creatinine 1 mg/dL, and INR 2.5. After 3 days of trimethoprim-sulfamethoxazole, a repeat INR is 5.2, and she reports persistent nose bleeding, which stops for a few hours but then restarts again.

QUESTION: What do you think is causing the laboratory abnormality? How should this patient’s condition be managed?

DISCUSSION: Trimethoprim–sulfamethoxazole inhibits cytochrome 2C9, the principal hepatic enzyme that catabolizes warfarin, decreases vitamin K–producing bacteria in the gastrointestinal tract, and displaces warfarin from its plasma protein-binding sites. A search of the medical literature documents multiple cases of enhanced warfarin effect when trimethoprim–sulfamethoxazole is taken concurrently.29,30

In this patient, the drug interaction occurred after trimethoprim–sulfamethoxazole was started. She is not taking any other medications that could cause the drug–laboratory test interaction and has no history of vitamin K deficiency or liver disease, which could be causing hypoprothrombinemia. To confirm that trimethoprim–sulfamethoxazole is causing the drug interaction, the physician could discontinue the drug and then see if her INR returns to the range of 2 to 3. However, because the trimethoprim–sulfamethoxazole–warfarin interaction is well known, a better approach might be to continue antibiotic treatment, hold warfarin until the INR has decreased to 2.5, and then resume warfarin at a reduced daily dose while the patient is taking antibiotic.

Tertiary literature includes reference texts, monograph databases, and review articles which provide appropriate foundational content and background material essential for understanding basic concepts and historical data relevant to the topic. Secondary literature is a gateway to primary literature, and it includes indexing and abstracting services (eg, PubMed). Primary literature includes case reports, experimental studies, and other nonreview types of articles in journals about the topic. These represent the most current literature on the topic. By systematically scanning the literature in this order, the clinician can be sure to have identified and analyzed all relevant literature, which is crucial in developing appropriate conclusions for these types of situations.

Tertiary Literature

Tertiary literature, which contains useful information about drug–laboratory test interferences, includes the Physicians’ Desk Reference. Each complete package insert included in this book contains a precautions section that includes information on drug–laboratory test interferences. However, it is important to note that the Physicians’ Desk Reference does not include package inserts on all commercially available drugs, nor does it include complete package inserts for all of the products included in the text. Also, manufacturers often do not update package insets with findings from current literature.27 Thus, additional resources will need to be checked (eg, DailyMed by the National Institutes of Health [http://dailymed.nlm.nih.gov/dailymed/]). DailyMed includes more than 95,000 package inserts. Also, the drug monographs in the AHFS Drug Information, published by the American Society of Health-System Pharmacists, include a section on laboratory test interferences. Although the information provided is brief, it can be used as an initial screen. This resource is available electronically by subscription from the American Society of Health-System Pharmacists (www.ahfsdruginformation.com) or from other online databases including First Databank (www.fdbhealth.com) or Lexicomp (www.wolterskluwer.com/en/solutions/lexicomp).

A variety of other books about clinical laboratory tests are provided (List 1). Some are comprehensive references while others are handbooks. All of them provide information about drug–laboratory test interferences. However, the reference texts are more complete than the handbooks. In addition, several comprehensive review articles include current information about drug–laboratory test interferences.

Micromedex Solutions, DynaMed Plus, Drugs.com, Facts and Comparisons, and Lexicomp, are all online searchable databases (List 2). For every drug included in the system, information is available in a drug monograph format, and any information about drug–laboratory test interferences is included in the monograph. Although not always listed separately as a laboratory test interference, the information may be included in the adverse reaction, warning, or monitoring section of the monograph. In addition, for some drugs, drug information questions and answers are included. To access relevant information, the clinician can search information using the name of the drug or the laboratory test. Often, the drug–laboratory test interference is assigned a severity rating (eg, major or minor interference) as an indication of its clinical significance, and references to primary literature are available so that the reader can learn more. These online databases vary in content completeness and ease of use.28 List 1 includes websites of commonly used databases for drug laboratory test interactions. In addition, some local clinical laboratory websites (eg, http://www.mayocliniclabs.com/test-info) may be convenient to access and use.25

List 1. Tertiary Resources

Books and Handbooks

  • Rifai N, Horvath AR, Wittwer CT. Tietz Fundamentals of Clinical Chemistry and Molecular Diagnostics. 8th ed. St. Louis, MO: Elsevier; 2019.

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  • DasGupta A, Hammett-Stabler CA, eds. Herbal Supplements: Efficacy, Toxicity, Interactions with Western Drugs and Effects on Lab Tests. Hoboken, NJ: Wiley; 2011.

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  • Laposata M, ed. Laboratory Medicine: The Diagnosis of Disease in the Clinical Laboratory. New York, NY: McGraw Hill Medical; 2018.

  • McPherson RA, Pincus MR, eds. Henry’s Clinical Diagnosis and Management by Laboratory Methods. 23rd ed. Philadelphia, PA: Elsevier WB Saunders; 2017.

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  • Rao LV, Snyder LM. Wallach’s Interpretation of Diagnostic Tests: Pathways to Arriving at a Clinical Diagnosis. 11th ed. Philadelphia, PA: Wolters Kluwer; 2021.

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  • Young DS. Effects of Preanalytic Variables on Clinical Laboratory Tests. 3rd ed. Washington, DC: American Association for Clinical Chemistry; 2007.

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  • Young DS. Effects of Drugs on Clinical Laboratory Tests. 5th ed. Washington, DC: American Association for Clinical Chemistry; 2000.

Review Articles

  • DasGupta A, Bernard DW. Herbal remedies: effects on clinical laboratory tests. Arch Pathol Lab Med. 2006; 130(4):521-528.

    This review summarizes literature from 1980 to 2005 on herbal drug interactions with laboratory tests. Mechanisms include (1) herbal agent-induced in vivo toxic effects, (2) direct assay interference by the herbal agent, or (3) contaminant in the herbal agent produces in vivo or in vitro effects that produce changes in laboratory test results. The effect of Chan su on digoxin blood levels and St. John’s wort on blood levels of cyclosporine, digoxin, theophylline, and protease inhibitors are just some of the herbal agent–laboratory test interactions discussed. This is a follow-up to the author’s first article on the topic, which was published in the American Journal of Clinical Pathology in 2003. As of 2021, this review has not been updated.

  • Kroll MH, Elin RJ. Interference with clinical laboratory analyses. Clin Chem 1994; 40(11 Pt 1):1996-2005.

    This is an excellent overview of drug–laboratory test interactions. The article describes how drugs, metabolites, and additives (eg, heparin and ethylenediamine tetra-acetic acid) can produce significant interactions and discrepancies during in vitro analytic procedures. It also provides a summary of useful references (although outdated) on the topic. In addition, a suggested approach to drug–laboratory test interactions is described.

  • Lopez A, Fraissinet F, Lefebvre H, et al. Pharmacological and analytical interference in hormone assays for diagnosis of adrenal incidentaloma. Ann Endocrinol 2019; 80(4):250-258.

    This is an excellent overview of patient-related factors, medications, and analytical factors that can interfere with laboratory tests for metanephrines, aldosterone, renin, cortisol, or corticosteroid binding globulin.

  • Montanelli L, Benvenga S, Hegedus L, et al. Drugs and other substances interfering with thyroid function. In: Vitti P, Hegedus L, eds. Thyroid Diseases. Chaim, Switzerland: Springer International Publishing; 2018:733-761. 10.1007/978-3-319-45013-1_27.

    This review discusses drugs that interfere with regulation of the hypothalamic-pituitary-thyroid axis and drugs that interfere with thyroid function. For each medication class included, the mechanism of the drug-laboratory test interaction is provided and, when available, the frequency of the interaction in treated patients, whether the interaction appears to be dose related, and the timeline for the interaction.

  • Sher PP. Drug interferences with clinical laboratory tests. Drugs 1982; 24(1):24-63.

    This useful reference provides many tables of drugs known to interfere with various laboratory tests. The data are arranged by laboratory test. For many common laboratory tests, summary tables of drugs known to interfere with the particular laboratory tests are provided. Also, mechanisms for the in vivo and in vitro interactions are described. Although this reference is dated and is not useful for newer drugs, it is an excellent resource for older drugs.

  • Sonntag O, Scholer A. Drug interference in clinical chemistry: recommendation of drugs and their concentrations to be used in drug interference studies. Ann Clin Biochem. 2001;38(Pt 4):376-385.

    In 1995, 18 clinical laboratory test experts identified 24 commonly used drugs known to interfere with laboratory tests. Usual therapeutic and toxic drug concentrations were identified. Both concentrations of each drug were added in vitro to blood and urine specimens and then various laboratory tests were run on the specimens. Laboratory testing was duplicated in three different laboratories. This review article summarizes drug–laboratory test interactions for more than 70 different laboratory tests.

  • Yao H, Rayburn ER, Shi Q, et al. FDA-approved drugs that interfere with laboratory tests: a systematic search of U.S. drug labels. Crit Rev Clin Lab Sci 2017;54(1):1-17.

    This includes two extensive listings of medications that affect urine and blood-based assays along with the authors’ review of the package labeling of more than 65,000 single ingredient medications. It is a useful reference.

List 2. Databases and Websites to Access Databases*

American Hospital Formulary Service Drug Information

www.ahfsdruginformation.com

DailyMed

https://dailymed/nlm.nih.gov/

DynaMed Plus

www.dynamed.com

Facts and Comparisons

www.factsandcomparisons.com

Lexicomp

www.wolterskluwer.com/en/solutions/lexicomp

Micromedex Solutions

http://www.micromedex.com

Prescribers’ Digital Reference

http://www.pdr.net

*A subscription may be required to access the resource.

Secondary and Primary Literature

For secondary literature, the main indexing or abstracting service that should be used is PubMed. This allows the clinician to check the literature from thousands of biomedical journals from 1946 to the present. Due to improvements in search capabilities, clinicians can search using text words (ie, words as they might appear in the title or abstract of a journal article). The database will automatically convert that text word to official medical subject headings or accepted indexing terms. As a result, search output is optimized despite the lack of proficiency or experience of the searcher. In addition, the database provides links enabling clinicians to locate related articles or order articles online, which enhance search capabilities and convenience in obtaining relevant primary literature articles.

This chapter does not allow a complete tutorial on developing search strategies, conducting PubMed searches, and evaluating primary literature. However, the reader is encouraged to develop expertise in this area so that he or she can identify current, relevant literature efficiently. A wide variety of tutorials and webcasts are available free of charge (https://www.ncbi.nlm.nih.gov/pubmed/).

SUMMARY

Although the number of drug–laboratory test interferences increases as the number of commercially available drugs increases, improved literature resources that compile information on this topic and improved assay methodologies have helped clinicians in dealing with suspected cases of this problem. Most drug–laboratory test interferences are due to in vivo effects of drugs; that is, the drug’s pharmacological or toxic effects produce specific alterations in laboratory values. A drug–laboratory test interference should be suspected whenever a laboratory test result does not match the signs and symptoms in a patient, when the results of different tests that assess the same organ function or drug effect conflict with each other, or when serial laboratory test values vary greatly over a short period of time or are inconsistent with expected results.

To determine if a drug is interfering with a drug–laboratory test, the clinician should, at a minimum, establish a temporal relationship between the change in the laboratory test and drug use; rule out other drugs and diseases as the cause; and discontinue the drug and repeat the laboratory test to see if dechallenge corrects the abnormal laboratory test. The literature should be checked to see if documentation of the drug–laboratory test interference can be found. The literature search should be systematic to ensure retrieval of the most comprehensive and current information. Therefore, the clinician should proceed from the tertiary to the secondary and then to the primary literature and use a variety of resources to arrive at a conclusion.

LEARNING POINTS

1. What are the differences between an in vivo and an in vitro drug interference with a laboratory test?

ANSWER: An in vivo interaction is characterized by an actual change in measured analyte concentration or activity prior to specimen collection and analysis. That is, the change in the measured analyte occurred in the patient and the laboratory test abnormality is true. An in vitro interaction is characterized by a drug’s physical presence in a body fluid or tissue specimen, which interferes with clinical laboratory testing during the analytical process. The interference occurs outside the patient’s body and after the specimen is collected from the patient.

2. What type of laboratory test is prone to in vitro drug interferences? If a drug laboratory test interaction is suspected, what options are available?

ANSWER: Radioimmunoassays are prone to in vitro drug interferences when cross reactions occur between the measured analyte and other substances in the specimen, which could include a drug’s metabolites, other chemically similar drugs, or heterophilic antibodies. If a drug-laboratory test interference is suspected, the clinician can explore the option of performing the laboratory test using a different assay method (eg, high performance liquid chromatography).

3. What key information should a clinician collect to confirm that a drug is causing a laboratory test interaction?

ANSWER: The four key criteria in confirming the presence of a drug–laboratory test interaction include the following:

  • Ensuring that the change in the laboratory test occurred after the drug was started

  • Ruling out other drugs as causes of the laboratory test change

  • Ruling out concurrent medical illness(es) as causes of the laboratory test change

  • Stopping the drug and seeing if the laboratory test result returns to the predrug value

4. What type of literature resource should a clinician access first to review foundational information on a drug’s adverse reaction profile and the likelihood that it could be causing an in vivo laboratory test abnormality?

ANSWER: Tertiary literature, which includes reference texts, review articles, and searchable databases, will provide good background information on medications. This information is helpful in understanding the primary literature on the topic.

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