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Open Access Highly Accessed Research article

Using molecular similarity to highlight the challenges of routine immunoassay-based drug of abuse/toxicology screening in emergency medicine

Matthew D Krasowski128*, Anthony F Pizon3, Mohamed G Siam4, Spiros Giannoutsos2, Manisha Iyer1 and Sean Ekins567

Author Affiliations

1 Department of Pathology, University of Pittsburgh, Pittsburgh, PA, USA

2 Department of Pathology, Division of Clinical Chemistry, Toxicology and Therapeutic Drug Monitoring Laboratory, University of Pittsburgh Medical Center Presbyterian/Shadyside, Pittsburgh, PA, USA

3 Department of Emergency Medicine, Division of Medical Toxicology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA

4 Department of Forensic Medicine and Toxicology, Zagazig University, Zagazig, Egypt

5 Collaborations in Chemistry, Jenkintown, PA, USA

6 Department of Pharmacology, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Piscataway, NJ, USA

7 Department of Pharmaceutical Sciences, University of Maryland, Baltimore, MD, USA

8 Department of Pathology (6233 RCP), The University of Iowa Hospitals and Clinics, 200 Hawkins Drive, Iowa City, IA 52242, USA

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BMC Emergency Medicine 2009, 9:5  doi:10.1186/1471-227X-9-5

Published: 28 April 2009

Abstract

Background

Laboratory tests for routine drug of abuse and toxicology (DOA/Tox) screening, often used in emergency medicine, generally utilize antibody-based tests (immunoassays) to detect classes of drugs such as amphetamines, barbiturates, benzodiazepines, opiates, and tricyclic antidepressants, or individual drugs such as cocaine, methadone, and phencyclidine. A key factor in assay sensitivity and specificity is the drugs or drug metabolites that were used as antigenic targets to generate the assay antibodies. All DOA/Tox screening immunoassays can be limited by false positives caused by cross-reactivity from structurally related compounds. For immunoassays targeted at a particular class of drugs, there can also be false negatives if there is failure to detect some drugs or their metabolites within that class.

Methods

Molecular similarity analysis, a computational method commonly used in drug discovery, was used to calculate structural similarity of a wide range of clinically relevant compounds (prescription and over-the-counter medications, illicit drugs, and clinically significant metabolites) to the target ('antigenic') molecules of DOA/Tox screening tests. These results were compared with cross-reactivity data in the package inserts of immunoassays marketed for clinical testing. The causes for false positives for phencyclidine and tricyclic antidepressant screening immunoassays were investigated at the authors' medical center using gas chromatography/mass spectrometry as a confirmatory method.

Results

The results illustrate three major challenges for routine DOA/Tox screening immunoassays used in emergency medicine. First, for some classes of drugs, the structural diversity of common drugs within each class has been increasing, thereby making it difficult for a single assay to detect all compounds without compromising specificity. Second, for some screening assays, common 'out-of-class' drugs may be structurally similar to the target compound so that they account for a high frequency of false positives. Illustrating this point, at the authors' medical center, the majority of positive screening results for phencyclidine and tricyclic antidepressants assays were explained by out-of-class drugs. Third, different manufacturers have adopted varying approaches to marketed immunoassays, leading to substantial inter-assay variability.

Conclusion

The expanding structural diversity of drugs presents a difficult challenge for routine DOA/Tox screening that limit the clinical utility of these tests in the emergency medicine setting.