Starting from the 1970s, therapeutic drug monitoring has evolved from monitoring concentrations of a few antiepileptic drugs to a major discipline in today's laboratory practice. For a drug with a narrow therapeutic range, therapeutic drug monitoring becomes an essential part of patient management, especially because of the development of immunoassays for measuring concentrations of drugs in a biological matrix. In current practice, 15-20 therapeutic drugs are routinely monitored even in medium-size clinical laboratories, and a list of well over 50 therapeutic drugs can be found in the laboratory test guides of major medical centers in the United States, academic medical centers, and reference laboratories. These centers not only employ immunoassays but also take advantage of sophisticated analytical techniques such as gas chromatog-raphy/mass spectrometry and high-performance liquid chromatography coupled with mass spectrometry for therapeutic drug-monitoring services.

Similarly, in the past two decades, drugs of abuse testing became a routine part of emergency room testing and clinical laboratory service. Federal and state governments, as well as the private sector, now recognize the necessity of a drug-free work environment. Moreover, drug testing is a routine part of law enforcement activity in crime and forensic laboratories. Strict laws are also enforced throughout the United States against driving under the influence of alcohol. Therefore, alcohol and drug testing is an important component of most toxicological laboratory services.

Hand book of Drug Monitoring attempts to bridge different analytical techniques used in today's practice of therapeutic drug monitoring and drugs of abuse as well as alcohol testing with relevant theory, mechanism, and in-depth scientific discussion on each topic. As a handbook at the bench of a clinical laboratory the book serves as a quick reference to find the potential source of a false-positive or a false-negative result. At the same time, this book is a reference for medical technologists, supervisors, laboratory directors, clinical chemists, toxicologists, and pathologists looking in-depth for the cause of a potential interference, as well as a guide to the tests that can be ordered to circumvent such problem.

The book has 22 chapters, 13 focusing on various issues of therapeutic drug monitoring, one on analysis of heavy metals, one on alcohol testing, and seven on issues of drugs of abuse testing. Chapters are written by experts in their relative subspecialties and also by the editor. I am grateful to this outstanding group of contributors because without their generosity and dedication this book would never have been written.

The chapters on therapeutic drug monitoring cover a wide range of topics from clinical utility of free drug monitoring to interferences in digoxin assay, and include issues in monitoring anticonvulsant drugs, immunosuppressants, tricyclic antidepres-sants, and antiretrovirals used in treating AIDS patients. One chapter is focussed on common interferences from endogenous substances such as bilirubin, hemoglobin, and lipids in immunoassays for therapeutic drugs. Another chapter is dedicated to interferences from heterophilic antibodies in therapeutic drug monitoring. Pharmacoge-nomics and personalized medicine is the future frontier of therapeutic drug monitoring. Chapter 11 is dedicated to this subject.

Use of complementary and alternative medicines by the general population is increasing steadily not only in the United States but also worldwide. Unexpected concentrations of therapeutic drugs because of use of complementary and alternative medicine have been well documented in the literature; for example, low concentrations of many therapeutic drugs because of self-medication with St. John's Wort, an herbal antidepressant. Chapter 13 is dedicated to important issues of drug-herb and drug-food interactions and their impact on therapeutic drug monitoring.

People try to beat drug tests to avoid consequences of a failed test. Chapter 17 discusses common household adulterants, as well as other adulterants such as nitrite, pyridinium chlorochromate, and glutaraldehyde, which people add in vitro to their urine to cheat on drug tests. Routine specimen integrity testing may not detect some adulterants, and practical tips are given in Chapter 17 to identify such adulterated specimens. There is much interference with drugs of abuse testing of the amphetamine class. Therefore, Chapter 20 addresses this important issue. Designer drugs and rave party drugs may escape detection in routine laboratory procedures for drugs of abuse testing. This topic and how to avoid such pitfalls are addressed in Chapter 19. Alternative specimens for drugs of abuse testing such as hair, saliva, sweat, and meconium are the topics of Chapter 18.

An analytic true positive may be a clinically false positive, for example, positive opiate test because of ingestion of poppy seed product. This important issue is addressed in Chapter 21, which will be helpful to medical review officers as well as to any toxicologist. Another chapter is dedicated to the topic of expert witness testimony by technologists performing alcohol and drugs of abuse testing and toxicologists supervising such tests, when often called as factual or expert witnesses in a court of law.

I express my sincere thanks to Robert L. Hunter, MD, PhD, Professor and Chairman, Department of Pathology and Laboratory Medicine, University of Texas-Houston Medical School, for his continued support for the last one-and-half years as I worked on this project. In addition, he critically read all chapters I wrote and made excellent recommendations for improvement. Alice Wells, MT(ASCP), read the entire manuscript and checked whether references were put in correct order and number and also helped me in editing this book. John Mohr, PharmD, assistant professor of internal medicine at our institution, reviewed therapeutic ranges and helped me with important suggestions. I also thank him. I also thank two of our pathology residents, Michelle Rodriguez, MD, and Anna Richmond, MD, for critically reading several chapters and making helpful suggestions. Last but not least, I express my thanks to my wife Alice for tolerating the long hours spent on this project and her continued support. Finally, readers will be the judge of the final success of this project. If they find this book helpful, we will feel our effort is well rewarded.

Amitava Dasgupta


Preface v

Contributors ix

1 Introduction to Therapeutic Drug Monitoring

Amitava Dasgupta 1

2 Monitoring Free Drug Concentration

Amitava Dasgupta 41

3 Analytical Techniques for Measuring Concentrations of Therapeutic Drugs in Biological Fluids

Amitava Dasgupta and Pradip Datta 67

4 The Pre-Analytical Phase of Drug Testing: From Specimen Collection to Analysis Catherine A. Hammett-Stabler 87

5 Effect of Hemolysis, High Bilirubin, Lipemia, Paraproteins, and System Factors on Therapeutic Drug Monitoring Pradip Datta 97

6 Digoxin: So Many Interferences and How to Eliminate Them

Amitava Dasgupta 111

7 Interferences with Measurement of Anticonvulsants

William Clarke 133

8 Pitfalls in Measuring Antidepressant Drugs

Uttam Garg 149

9 Immunosuppressive Drugs: Pharmacokinetics, Preanalytic Variables, and Analytical Considerations Anthony W. Butch 165

10 Therapeutic Drug Monitoring in Human Immunodeficiency Virus/Acquired

Immunodeficiency Syndrome Steven J. Soldin 201

11 Pharmacogenomics and Personalized Medicine: Issues and Methodology

Steven H. Y. Wong 211

12 Interference of Heterophilic and Other Antibodies in Measurement of Therapeutic

Drugs by Immunoassays Pradip Datta 225

13 Drug-Herb and Drug-Food Interactions: Impact on Therapeutic Drug Monitoring Amitava Dasgupta 235

14 Toxic Element Testing with Clinical Specimens

Gwendolyn A. McMillin and Joshua A. Bornhorst 263

15 Alcohol Testing

Steve C. Kazmierczak and Hassan M. E. Azzazy 283

16 Introduction to Drugs of Abuse Testing

Tai C. Kwong 297

17 Urinary Adulterants and Drugs of Abuse Testing

Amitava Dasgupta 317

18 Hair, Oral Fluid, Sweat, and Meconium Testing for Drugs of Abuse:

Advantages and Pitfalls Uttam Garg 337

19 Abused and Designer Drugs and How They Escape Detection

Barry Levine and Rebecca Jufer-Phipps 365

20 Interpretation of Amphetamines Screening and Confirmation Testing

Larry Broussard 379

21 Clinical False-Positive Drug Test Results

Tai C. Kwong 395

22 Providing Expert Witness for Alcohol and Positive Drugs of Abuse Test Results Andrea Terrell, William Clarke, Michael Evans, and Jennifer Collins 407

Index 421

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