A Study of Opiate, Opiate Metabolites and Antihistamines in Urine after Consumption of Cold Syrups by LC-MS/MS
Abstract
:1. Introduction
2. Results and Discussion
2.1. Method Development and Assay Validation
2.2. Clinical Trials Study
3. Materials and Methods
3.1. Chemicals
3.2. Urine Samples
3.2.1. Clinical Trial Urine Samples
3.2.2. Urine Samples from Real Cases
3.3. Preparation of Solutions
3.4. Apparatus
3.5. Method and Validation
3.5.1. Analytical Strategy
3.5.2. Dynamic Ranges, LOQs, and LODs
3.5.3. Selectivity
3.5.4. Accuracy and Precision
3.5.5. Carryover
3.5.6. Matrix Effect
3.5.7. Interferences Study
3.5.8. Dilution Integrity
3.5.9. Stability
3.5.10. Clinical Trials Study
3.5.11. Real Case Study
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
- National Drug Overdose Deaths through 2017. Available online: https://d14rmgtrwzf5a.cloudfront.net/sites/default/files/national_drug_overdose_deaths_through_2017.pdf (accessed on 15 October 2019).
- Meadway, C.; George, S.; Braithwaite, R. A rapid GC–MS method for the determination of dihydrocodeine, codeine, norcodeine, morphine, normorphine and 6-MAM in urine. Forensic Sci. Int. 2002, 127, 136–141. [Google Scholar] [CrossRef]
- Orfanidis, A.; Mastrogianni, O.; Koukou, A.; Psarros, G.; Gika, H.; Theodoridis, G.; Raikos, N. A GC–MS method for the detection and quantitation of ten major drugs of abuse in human hair samples. J. Chromatogr. B 2017, 1047, 141–150. [Google Scholar] [CrossRef]
- Polettini, A.; Groppi, A.; Montagna, M. Rapid and highly selective GC/MS/MS detection of heroin and its metabolites in hair. Forensic Sci. Int. 1993, 63, 217–225. [Google Scholar] [CrossRef]
- Saad, M.A.A.; Abu-Rumman, A.M.; Mohamed, K.M. A gas chromatography–triple quadrupole mass spectrometry assay for the quantification of opiates in human blood samples. J. Anal. Toxicol. 2018, 43, 188–195. [Google Scholar] [CrossRef] [PubMed]
- Chiang, C.-H.; Lee, H.-H.; Chen, B.-H.; Lin, Y.-C.; Chao, Y.-Y.; Huang, Y.-L. Using ambient mass spectrometry and LC–MS/MS for the rapid detection and identification of multiple illicit street drugs. J. Food Drug Anal. 2019, 27, 439–450. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Krotulski, A.J.; Mohr, A.L.A.; Friscia, M.; Logan, B.K. Field detection of drugs of abuse in oral fluid using the Alere™ DDS®2 Mobile Test System with confirmation by liquid chromatography tandem mass spectrometry (LC–MS/MS). J. Anal. Toxicol. 2018, 42, 170–176. [Google Scholar] [CrossRef] [PubMed]
- Milne, R.W.; Nation, R.L.; Somogyi, A.A. The disposition of morphine and its 3- and 6-glucuronide metabolites in humans and animals, and the importance of the metabolites to the pharmacological effects of morphine. Drug Metab. Rev. 1996, 28, 345–472. [Google Scholar] [CrossRef]
- Vree, T.B.; Verwey-Van Wissen, C.P. Pharmacokinetics and metabolism of codeine in humans. Biopharm. Drug Dispos. 1992, 13, 445–460. [Google Scholar] [CrossRef]
- Smith, M.L.; Nichols, D.C.; Underwood, P.; Fuller, Z.; Moser, M.A.; LoDico, C.; Gorelick, D.A.; Newmeyer, M.N.; Concheiro, M.; Huestis, M.A. Morphine and codeine concentrations in human urine following controlled poppy seeds administration of known opiate content. Forensic Sci. Int. 2014, 241, 87–90. [Google Scholar] [CrossRef] [Green Version]
- Lachenmeier, D.W.; Sproll, C.; Musshoff, F. Poppy seed foods and opiate drug testing—where are we today? Drug Monit. 2010, 32, 11–18. [Google Scholar] [CrossRef]
- Meadway, C.; George, S.; Braithwaite, R. Opiate concentrations following the ingestion of poppy seed products—Evidence for ‘the poppy seed defence’. Forensic Sci. Int. 1998, 96, 29–38. [Google Scholar] [CrossRef]
- Dinis-Oliveira, R.J. Metabolism and metabolomics of opiates: A long way of forensic implications to unravel. J. Forensic Leg. Med. 2019, 61, 128–140. [Google Scholar] [CrossRef] [PubMed]
- Ellis, A.D.; McGwin, G.; Davis, G.G.; Dye, D.W. Identifying cases of heroin toxicity where 6-acetylmorphine (6-AM) is not detected by toxicological analyses. Forensic Sci. Med. Pathol. 2016, 12, 243–247. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Selavka, C. Poppy seed ingestion as a contributing factor to opiate-positive urinalysis results: The Pacific perspective. J. Forensic Sci. 1991, 36, 685–696. [Google Scholar] [CrossRef] [PubMed]
- Fraser, A.D.; Worth, D. Experience with a urine opiate screening and confirmation cutoff of 2000 ng/mL. J. Anal. Toxicol. 1999, 23, 549–551. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Chen, P.; Braithwaite, R.A.; George, C.; Hylands, P.J.; Parkin, M.C.; Smith, N.W.; Kicman, A.T. The poppy seed defense: A novel solution. Drug Test. Anal. 2014, 6, 194–201. [Google Scholar] [CrossRef]
- Guo, B.B.; Zhang, Y.Q.; Wang, S.F.; Ding, J.S.; Zhou, W.H. The pharmacokinetics of morphine and codeine in human plasma and urine after oral administration of Qiangli Pipa Syrup. J. Forensic Sci. 2018, 63, 1221–1228. [Google Scholar] [CrossRef]
- Samano, K.L.; Clouette, R.E.; Rowland, B.J.; Sample, R.H.B. Concentrations of morphine and codeine in paired oral fluid and urine specimens following ingestion of a poppy seed roll and raw poppy seeds. J. Anal. Toxicol. 2015, 39, 655–661. [Google Scholar] [CrossRef]
- Konstantinova, S.V.; Normann, P.T.; Arnestad, M.; Karinen, R.; Christophersen, A.S.; Mørland, J. Morphine to codeine concentration ratio in blood and urine as a marker of illicit heroin use in forensic autopsy samples. Forensic Sci. Int. 2012, 217, 216–221. [Google Scholar] [CrossRef]
- Ceder, G.; Jones, A.W. Concentration ratios of morphine to codeine in blood of impaired drivers as evidence of heroin use and not medication with codeine. Clin. Chem. 2001, 47, 1980–1984. [Google Scholar] [CrossRef] [Green Version]
- Schuppener, L.M.; Corliss, R.F. Death due to complications of bowel obstruction following raw poppy seed ingestion. J. Forensic Sci. 2018, 63, 614–618. [Google Scholar] [CrossRef] [PubMed]
- Croitoru, M.D.; Fülöp, I.; Irimia-Constantin, M.R.; Varga, E.; Kelemen, H.; Fogarasi, E.; Faliboga, L.M. The risk of using poppy seed tea made from several varieties available on the romanian market. Acta Med. Marisiensis 2017, 63, 62–65. [Google Scholar] [CrossRef] [Green Version]
- EFSA Panel on Contaminants in the Food Chain (CONTAM). Scientific opinion on the risks for public health related to the presence of opium alkaloids in poppy seeds. Efsaj 2011, 9, 2405. [Google Scholar] [CrossRef]
- López, P.; Pereboom-de Fauw, D.P.K.H.; Mulder, P.P.J.; Spanjer, M.; de Stoppelaar, J.; Mol, H.G.J.; de Nijs, M. Straightforward analytical method to determine opium alkaloids in poppy seeds and bakery products. Food Chem. 2018, 242, 443–450. [Google Scholar] [CrossRef]
- Gardiner, S.J.; Chang, A.B.; Marchant, J.M.; Petsky, H.L. Codeine versus placebo for chronic cough in children. Cochrane Database Syst. Rev. 2016, 7, CD011914. [Google Scholar] [CrossRef] [Green Version]
- Huang, W.; Qiu, Q.; Chen, M.; Shi, J.; Huang, X.; Kong, Q.; Long, D.; Chen, Z.; Yan, S. Determination of 18 antibiotics in urine using LC-QqQ-MS/MS. J. Chromatogr. B 2019, 1105, 176–183. [Google Scholar] [CrossRef]
- Mercolini, L.; Protti, M.; Catapano, M.C.; Rudge, J.; Sberna, A.E. LC-MS/MS and volumetric absorptive microsampling for quantitative bioanalysis of cathinone analogues in dried urine, plasma and oral fluid samples. J. Pharm. Biomed. Anal. 2016, 123, 186–194. [Google Scholar] [CrossRef]
- Tan, B.; Yang, A.; Yuan, W.; Li, Y.; Jiang, L.; Jiang, J.; Qiu, F. Simultaneous determination of glipizide and its four hydroxylated metabolites in human urine using LC-MS/MS and its application in urinary phenotype study. J. Pharm. Biomed. Anal. 2017, 139, 179–186. [Google Scholar] [CrossRef]
- Kachingwe, B.H.; Uang, Y.S.; Huang, T.J.; Wang, L.H.; Lin, S.J. Development and validation of an LC-MS/MS method for quantification of NC-8 in rat plasma and its application to pharmacokinetic studies. J. Food Drug Anal. 2018, 26, 401–408. [Google Scholar] [CrossRef] [Green Version]
- Cao, Z.; Kaleta, E.; Wang, P. Simultaneous quantitation of 78 drugs and metabolites in urine with a dilute-and-shoot LC-MS-MS assay. J. Anal. Toxicol. 2015, 39, 335–346. [Google Scholar] [CrossRef] [Green Version]
- Scientific Working Group for Forensic Toxicology. Scientific working group for forensic toxicology (SWGTOX) standard practices for method validation in forensic toxicology. J. Anal. Toxicol. 2013, 37, 452–474. [Google Scholar] [CrossRef] [PubMed]
- Kmellar, B.; Fodor, P.; Pareja, L.; Ferrer, C.; Martinez-Uroz, M.A.; Valverde, A.; Fernandez-Alba, A.R. Validation and uncertainty study of a comprehensive list of 160 pesticide residues in multi-class vegetables by liquid chromatography-tandem mass spectrometry. J. Chromatogr. A 2008, 1215, 37–50. [Google Scholar] [CrossRef] [PubMed]
- Ferrer, C.; Lozano, A.; Agüera, A.; Girón, A.J.; Fernández-Alba, A. Overcoming matrix effects using the dilution approach in multiresidue methods for fruits and vegetables. J. Chromatogr. A 2011, 1218, 7634–7639. [Google Scholar] [CrossRef] [PubMed]
- Shin, Y.; Lee, J.; Lee, J.; Lee, J.; Kim, E.; Liu, K.H.; Lee, H.S.; Kim, J.H. Validation of a multiresidue analysis method for 379 pesticides in human serum using liquid chromatography-tandem mass spectrometry. J. Agric. Food Chem. 2018, 66, 3550–3560. [Google Scholar] [CrossRef]
- Kloepfer, A.; Quintana, J.B.; Reemtsma, T. Operational options to reduce matrix effects in liquid chromatography-electrospray ionization-mass spectrometry analysis of aqueous environmental samples. J. Chromatogr. A 2005, 1067, 153–160. [Google Scholar] [CrossRef]
- Svan, A.; Hedeland, M.; Arvidsson, T.; Pettersson, C.E. The differences in matrix effect between supercritical fluid chromatography and reversed phase liquid chromatography coupled to ESI/MS. Anal. Chim. Acta 2018, 1000, 163–171. [Google Scholar] [CrossRef]
- Eeckhaut, A.V.; Lanckmans, K.; Sarre, S.; Smolders, I.; Michotte, Y. Validation of bioanalytical LC-MS/MS assays: Evaluation of matrix effects. J. Chromatogr. B Anal. Technol. Biomed. Life Sci. 2009, 877, 2198–2207. [Google Scholar] [CrossRef]
- Perez, E.R.; Knapp, J.A.; Horn, C.K.; Stillman, S.L.; Evans, J.E.; Arfsten, D.P. Comparison of LC-MS-MS and GC-MS analysis of benzodiazepine compounds included in the drug demand reduction urinalysis program. J. Anal. Toxicol. 2016, 40, 201–207. [Google Scholar] [CrossRef] [Green Version]
- Lafolie, P.; Beck, O.; Lin, Z.; Albertioni, F.; Boréus, L. Urine and plasma pharmacokinetics of codeine in healthy volunteers: Implications for drugs-of-abuse testing. J. Anal. Toxicol. 1996, 20, 541–546. [Google Scholar] [CrossRef] [Green Version]
- Wiffen, P.; Wee, B.; Moore, R.A. Oral morphine for cancer pain. Cochrane Database Syst. Rev. 2016, 2016, CD003868. [Google Scholar] [CrossRef]
- Bandieri, E.; Romero, M.; Ripamonti, C.I.; Artioli, F.; Sichetti, D.; Fanizza, C.; Santini, D.; Cavanna, L.; Melotti, B.; Conte, P.F.; et al. Randomized trial of low-dose morphine versus weak opioids in moderate cancer pain. J. Clin. Oncol. 2016, 34, 436–442. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Gulideline on Bioanalytical Method Validation. Available online: https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-bioanalytical-method-validation_en.pdf (accessed on 20 June 2018).
- Bioanalytical Method Validation Guidance for Industry. Available online: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/bioanalytical-method-validation-guidance-industry (accessed on 20 June 2018).
Sample Availability: Samples of the compounds are not available from the authors. |
Compound | Morphine | 6-AM | M3G | M6G | Codeine | C6G | Chlorpheniramine | Carbinoxamine |
---|---|---|---|---|---|---|---|---|
Internal standard | Morphine-d6 | Morphine-d6 | Morphine-d6 | Morphine-d6 | Codeine-d6 | Codeine-d6 | Chlorpheniramine-d6 | Chlorpheniramine-d6 |
R2 | 0.998 | 0.998 | 0.997 | 0.999 | 0.997 | 0.998 | 0.999 | 0.999 |
Linear range (ng mL−1) | 2.5–800 | 2.5–1000 | 2.5–800 | 2.5–600 | 2.5–1000 | 2.5–600 | 2.5–1000 | 2.5–1000 |
LOD (ng mL−1) | 1.3 | 0.5 | 0.4 | 0.5 | 0.6 | 0.2 | 0.2 | 0.3 |
Carryover (%) | −0.03 | 0.03 | 0.01 | 0.01 | −0.01 | −0.03 | 0.01 | −0.01 |
Accuracy for QC (%) a | ||||||||
Intraday (n = 3) | ||||||||
QC-Low | 89.6 | 88.3 | 89.4 | 86.4 | 89.2 | 83.8 | 83.2 | 83.1 |
QC-Medium | 102.3 | 112.2 | 92.4 | 88.2 | 103.5 | 84.2 | 97.7 | 98.4 |
QC-High | 108.3 | 110.0 | 99.4 | 93.1 | 102.5 | 88.5 | 100.6 | 101.2 |
Interday (n = 3) | ||||||||
QC-Low | 88.8 | 88.5 | 86.3 | 85.8 | 87.8 | 84.1 | 85.3 | 85.3 |
QC-Medium | 98.9 | 104.6 | 92.7 | 90.2 | 100.9 | 89.0 | 98.0 | 98.4 |
QC-High | 104.0 | 103.9 | 100.4 | 95.8 | 101.2 | 96.2 | 100.2 | 100.4 |
Precision for QC (%) b | ||||||||
Intraday (n = 3) | ||||||||
QC-Low | 3.6 | 3.0 | 3.2 | 2.8 | 1.1 | 1.7 | 0.6 | 0.2 |
QC-Medium | 1.0 | 0.2 | 0.8 | 3.3 | 0.4 | 2.1 | 0.2 | 0.8 |
QC-High | 1.8 | 0.9 | 1.7 | 3.1 | 1.3 | 1.3 | 0.7 | 1.5 |
Interday (n = 3) | ||||||||
QC-Low | 4.2 | 2.9 | 4.1 | 3.2 | 1.8 | 2.5 | 3.9 | 4.0 |
QC-Medium | 4.6 | 6.2 | 3.5 | 8.3 | 2.3 | 7.6 | 1.4 | 1.7 |
QC-High | 3.7 | 4.5 | 1.7 | 4.5 | 1.6 | 6.2 | 0.9 | 1.1 |
Case No. | Morphine | 6-AM | M3G | M6G | Codeine | C6G | Chlo. | Carb. | M/C b |
---|---|---|---|---|---|---|---|---|---|
1 | 63 | 81 | N.D. c | 1104 | 3.0 | 16 | N.D. | N.D. | 62 |
2 | 53 | N.D. | 14 | 990 | 81 | 4.1 | N.D. | N.D. | 8 |
3 | 73 | N.D. | 3116 | 45 | 23 | 132 | N.D. | N.D. | 19 |
4 a | > 16000 | N.D. | > 16000 | 3527 | 3718 | 2454 | N.D. | N.D. | > 5 |
5 a | 11422 | N.D. | > 16000 | 1365 | 1519 | 2024 | N.D. | N.D. | > 8 |
6 | 1963 | 480 | 14339 | 747 | 792 | 1416 | N.D. | N.D. | 7 |
7 | 505 | N.D. | 11051 | 127 | 92 | 198 | N.D. | N.D. | 34 |
8 a | 3686 | N.D. | 510 | > 12000 | 291 | 273 | N.D. | N.D. | > 25 |
9 | N.D. | N.D. | N.D. | N.D. | N.D. | 5.6 | 38 | N.D. | 0 |
10 | N.D. | N.D. | 11 | N.D. | 8.9 | 10 | 8.7 | N.D. | 0.4 |
11 | 2.7 | N.D. | N.D. | N.D. | N.D. | N.D. | 337 | N.D. | ∞d |
12 | 208 | N.D. | 41 | 7182 | 111 | 89 | 21 | N.D. | 28 |
13 a | > 16000 | 12 | 9388 | > 12000 | 1836 | 3037 | 4.3 | N.D. | > 8 |
14 a | > 16000 | N.D. | 3793 | > 12000 | 3925 | 2683 | 122 | N.D. | > 5 |
15 a | > 16000 | 6722 | > 16000 | > 12000 | 7029 | 10838 | 63 | N.D. | > 3 |
© 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
Share and Cite
Yen, Y.-T.; Chang, Y.-J.; Lai, P.-J.; Chang, C.-L.; Chen, T.-Y.; Chyueh, S.-C. A Study of Opiate, Opiate Metabolites and Antihistamines in Urine after Consumption of Cold Syrups by LC-MS/MS. Molecules 2020, 25, 972. https://doi.org/10.3390/molecules25040972
Yen Y-T, Chang Y-J, Lai P-J, Chang C-L, Chen T-Y, Chyueh S-C. A Study of Opiate, Opiate Metabolites and Antihistamines in Urine after Consumption of Cold Syrups by LC-MS/MS. Molecules. 2020; 25(4):972. https://doi.org/10.3390/molecules25040972
Chicago/Turabian StyleYen, Yao-Te, Yin-Jue Chang, Pin-Jung Lai, Chi-Lun Chang, Ting-Yueh Chen, and San-Chong Chyueh. 2020. "A Study of Opiate, Opiate Metabolites and Antihistamines in Urine after Consumption of Cold Syrups by LC-MS/MS" Molecules 25, no. 4: 972. https://doi.org/10.3390/molecules25040972