MSACL 2018 US Abstract

Topic: Cannabinoids

The Grapefruit Effect: Identifying Potential Drug-Food Interactions in Patients Through Mass-Spectrometric Urinary Furanocoumarin Detection

David Schwope (Presenter)
Aegis Sciences Corporation

Bio: David Schwope is Manager, Research Scientists at Aegis Sciences Corporation. David obtained a Ph.D. in toxicology from the University of Maryland under Dr. Marilyn Huestis and has contributed to more than 20 research articles focusing primarily on human cannabinoid pharmacokinetics and pharmacodynamics. David is a member of the Society of Forensic Toxicologists, the American Academy of Forensic Sciences, and the American Chemical Society. He is a past recipient of the American Academy of Forensic Sciences Toxicology Section Irving Sunshine Award and the Society of Forensic Toxicologists Experimental Design in Toxicology Award. His current research interests include isotope ratio mass spectrometry and its applications to sports doping and forensic toxicology as well as large-panel LCMSMS testing in clinical toxicology. He lives in Nashville with his wife and children.

Authorship: David M. Schwope, Rebecca Heltsley
Aegis Sciences Corporation, Nashville, TN

Short Abstract

Furanocoumarin effects on metabolism of cytochrome P450 subtype 3A4 (CYP3A4) substrates have been well documented (e.g. “grapefruit effect”) and are of significant concern for numerous xenobiotics. To our knowledge, no clinical laboratories are routinely testing for furanocoumarin consumption. As part of a drug-drug interaction urine testing profile, we examined the prevalence of furanocoumarins in chronic pain, addiction treatment and mental health patients. A total of 27218 urines were obtained over 10 weeks and analyzed by LC-MS/MS. Furanocoumarins (either dihydroxybergamottin [LOD 10 ng/mL] or bergaptol [LOD 50 ng/mL]) were identified in 1165 samples (4.3%). Although urine detection cannot provide direct evidence of enzyme inhibition, these data provide beneficial insight regarding furanocoumarin prevalence and potential consequences on CYP3A4 substrate metabolism.

Long Abstract

Introduction

The effect of furanocoumarin consumption on metabolism of cytochrome P450 subtype 3A4 (CYP3A4) substrates has been well documented and is of significant concern for numerous xenobiotics.(1) Alteration of metabolism can lead to decreased efficacy and/or increased toxicity, depending on the specific substrate and enzyme inhibition level.(2) In addition, altered metabolism can result in differences in medication adherence determinations, particularly in instances where comprehensive metabolite profiling is not practical or available.(2,3) To our knowledge, no clinical laboratories are routinely testing for furanocoumarin consumption in either inpatient or outpatient settings, raising the potential for concern regarding the effects of this class of compounds on therapeutic treatments.

Methods

As part of a drug-drug interaction urine testing profile, we examined the prevalence of furanocoumarins in chronic pain, addiction treatment and mental health patients. The study was IRB-approved. Furanocoumarin analytes were extracted from 0.4 mL human urine by solid-phase extraction (SPE) and analyzed by liquid chromatography-tandem mass spectrometry under reverse-phase chromatographic conditions. Ionization was achieved by electrospray (positive mode) with qualitative (scheduled) MRM-mode detection and quantification. Conservative limits of detection were 10 ng/mL for dihydroxybergamottin (DHB) and 50 ng/mL for bergaptol. Bergamottin was not observed in urine during pilot testing (similar to other studies)(4) and was not included in the assay. All results were de-identified as part of the database extraction.

Results

A total of 27218 urines were obtained over 10 weeks and analyzed. Furanocoumarins (either DHB or bergaptol) were identified in 1165 samples (4.3%). Further results analysis are ongoing.

Conclusions & Discussion

Furanocoumarins have been shown to be present in high quantities in grapefruit and other forms of citrus(5), leading to the inclusion of concomitant grapefruit consumption warnings for numerous medications. While much is understood regarding grapefruit consumption and effects on medication, several other foods and beverages have been shown to contain furanocoumarins, further complicating both abstinence (for patients) and assessment of intake (for clinicians).(6) Urine detection provides an objective assessment of furanocoumarin intake (regardless of source), facilitating assessment of altered medication metabolism.

For the first time, the prevalence of furanocoumarins in a large outpatient population is examined. In addition, we provide preliminary results regarding observed impacts on urine drug metabolite detection in the presence of furanocoumarins. Although detection of furanocoumarins in urine cannot provide determination of enzyme inhibition, impacts on urine drug testing could be substantial, including false-negative adherence determinations. We intend to further examine the potential relationship between furanocoumarin detection and effects on metabolism as determined through urine metabolite analysis.


References & Acknowledgements:

1. Bailey DG, Arnold JMO, Spence JD. Grapefruit juice and drugs: how significant is the interaction? Clin Pharmacokin. Feb 1994;26(2):91-8.

2. Nieminen TH, Hagelberg NM, Saari TI, et al. Grapefruit juice enhances the exposure to oral oxycodone. Basic Clin Pharmacol Toxicol. Oct 2010;107(4):782-788.

3. Benmebarek M, Devaud C, Gex-Fabry M, et al. Effects of grapefruit juice on the pharmacokinetics of the enantiomers of methadone. Clin Pharmacol Ther. Jul 2004;76(1):55-63.

4. Lee SG, Kim k, Vance TM, et al. Development of a comprehensive analytical method for furanocoumarins in grapefruit and their metabolites in plasma and urine using UPLC-MC/MC: a preliminary study. Int. J. Food Sci. Nutr. Jul 2016; 67: 881-7.

5. Melough M, Vance TM, Lee SG, et al. Furocoumarin kinetics in plasma and urine of healthy adults following consumption of grapefruit (citrus paradise macf.) and grapefruit juice. J. Agric. Food Chem. 2017; 65: 3006-12.

6. Melough MM, Lee SG, Cho E, Kim K, Provatas AA, Perkins C. et al. Identification and Quantification of furanocoumarins in popularly consumed foods in the U.S. using QuEChERS extraction coupled with UPLC-MS/MS analysis. J Agric Food Chem. 2017; 65: 5049-55.


Financial Disclosure

DescriptionY/NSource
Grantsno
SalaryyesAegis Sciences Corporation
Board Memberno
Stockno
Expensesno

IP Royalty: no

Planning to mention or discuss specific products or technology of the company(ies) listed above:

yes