Cathine and cathinone disposition kinetics and neurotransmitter profile in several organs of rats exposed to a single dose of Catha edulis (Vahl) Forssk. ex Endl. extract

Ahmad M. Alamir; Mohammed A. Jeraiby; Hesham M. Korashy; Emad Sayed Shaheen; Mohammad A. Attafi; Magbool E. Oraiby; Ahmed M. Hakami; Mohammed Y. Albeishy; Ibrahim A. Khardali; Ismail A. Juraybi; Abeer A. Alobaida; Ibraheem M. Attafi

doi:10.1515/dmpt-2022-0154

Article

Cathine and cathinone disposition kinetics and neurotransmitter profile in several organs of rats exposed to a single dose of Catha edulis (Vahl) Forssk. ex Endl. extract

Ahmad M. Alamir , Mohammed A. Jeraiby , Hesham M. Korashy , Emad Sayed Shaheen , Mohammad A. Attafi , Magbool E. Oraiby , Ahmed M. Hakami , Mohammed Y. Albeishy , Ibrahim A. Khardali , Ismail A. Juraybi , Abeer A. Alobaida and Ibraheem M. Attafi

Published/Copyright: March 9, 2023

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From the journal Drug Metabolism and Personalized Therapy Volume 38 Issue 2

Abstract

Objectives

Catha edulis (Vahl) Forssk. ex Endl. (Khat) is a stimulant plant that contains cathine and cathinone, which its abuses induce euphoria, alertness, and motor activity. Since the toxicokinetics of these substances remain unclear, this study was carried out to investigate the disposition kinetics of cathine and cathinone, the neurotransmitter profile, following a single dose of C. edulis extract in rats.

Methods

Twenty-four adult male Wistar albino rats (250–300 g) were randomly selected and divided into six groups of four rats each. All groups received a single oral dose of 2,000 mg/kg body weight, and blood and tissue samples from the brain, lung, heart, liver, and kidney were obtained at intervals of 0.5, 1, 2.5, 5, 12, and 24 h. The cathine and cathinone concentrations were identified and quantified using ion trap ultra-high performance liquid chromatography (HPLC-IT/MS). The neurotransmitter profile was detected using the quadrupole time of flight UPLC-QTOF/MS method.

Results

The lung, liver, and heart tissues attained the highest levels of cathine, while the highest level of cathinone was determined in the heart. Cathine and cathinone concentrations in the blood and heart peaked at 0.5 h. The concentrations peaked in the brain 2.5 h later, indicating that the heart had an immediate effect, whereas the brain had a longer-lasting one. They have longer half-lives (2.68 and 5.07 h, respectively) and may remain in the brain for longer durations (3.31 and 2.31 h, respectively). The neurotransmitters epinephrine, dopamine, norepinephrine, and serotonin were detected in a delayed, prolonged and organ-specific manner.

Conclusions

Cathine and cathinone were deposited in considerable concentrations in all tissues analyzed, with the highest C_max in the lung and T_max in the heart tissues but not in the brain. In addition, neurotransmitters such as adrenaline, dopamine, norepinephrine, and serotonin were differentially detected in all tested samples in a organ-specific fashion. More study is needed to identify cathine and cathinone’s effects on neurotransmitter profiles. Nevertheless, these findings provided a further basis for experimental, clinical, and forensic investigations.

Keywords: Catha edulis ; cathine; cathinone; disposition; HPLC-IT/MS; kinetics; UPLC-QTOF/MS

Corresponding author: Ibraheem M. Attafi, PhD, Poison Control and Medical Forensic Chemistry Center, Jazan Health Affairs, Ministry of Health, P.O. Box 263, Jazan 45142, Saudi Arabia, Phone: +9661 7 324 1552, Fax: +9661 7 321 2301, Mobile: +9661 59161 0440, +9661 55851 8883, E-mail: iattafi@moh.gov.sa

Acknowledgments

The authors thank the Medical Research Center, Jazan University, Ministry of Education and Poison Control and Medical Forensic Chemistry Center, Jazan Health Affairs, Ministry of Health in Saudi Arabia for their collaboration and contributions to this study.

Research funding: None declared.
Author contributions: All authors have accepted responsibility for the entire content of this manuscript and approved its submission.
Competing interests: Authors state no conflict of interest.
Informed consent: Non applicable.
Ethical approval: This study was reviewed and approved by the Jazan Health Ethics Committee, Jazan, Saudi Arabia.

References

1. Drug Enforcement Administration. Drugs of abuse, a DEA resource guide: 2020 edition. Springfield, VA, USA: Drug Enforcement Administration, U.S. Department of Justice; 2020. https://www.dea.gov/sites/default/files/2020-04/Drugs%20of%20Abuse%202020-Web%20Version-508%20compliant-4-24-20_0.pdf [Accessed 28 September 2022].Search in Google Scholar

2. Dewick, PM. Medicinal natural products: a biosynthetic approach, 3rd ed. Hoboken, NJ, USA: John Wiley & Sons; 2009.10.1002/9780470742761Search in Google Scholar

3. Halbach, H. Medical aspects of the chewing of Khat leaves. Bull World Health Organ 1972;47:21.Search in Google Scholar

4. Al-Habori, M. The potential adverse effects of habitual use of Catha edulis (khat). Expet Opin Drug Saf 2005;4:1145–54. https://doi.org/10.1517/14740338.4.6.1145.Search in Google Scholar PubMed

5. Kalix, P. Khat: scientific knowledge and policy issues. Br J Addict 1987;82:47–53. https://doi.org/10.1111/j.1360-0443.1987.tb01436.x.Search in Google Scholar PubMed

6. Attafi, IM, Albeishy, MY, Hakami, AM, Attafi, MA, Khardali, IA. Habitual khat chewing alters urinary inorganic profile in adult healthy males. Drug Metabol Pers Ther 2021;36:295–8. https://doi.org/10.1515/dmpt-2020-0161.Search in Google Scholar PubMed

7. Cox, G, Rampes, H. Adverse effects of khat: a review. Adv Psychiatr Treat 2003;9:456–63. https://doi.org/10.1192/apt.9.6.456.Search in Google Scholar

8. Pélissier-Alicot, A-L, Gaulier, J-M, Champsaur, P, Marquet, P. Mechanisms underlying postmortem redistribution of drugs: a review. J Anal Toxicol 2003;27:533–44. https://doi.org/10.1093/jat/27.8.533.Search in Google Scholar PubMed

9. Nencini, P, Ahmed, AM. Khat consumption: a pharmacological review. Drug Alcohol Depend 1989;23:19–29. https://doi.org/10.1016/0376-8716(89)90029-x.Search in Google Scholar PubMed

10. Zelger, J, Carlini, E. Influence of cathinone (α-aminopropiophenone) and cathine (phenylpropanolamine) on circling behavior and on the uptake and release of [3H] dopamine in striatal slices of rats. Neuropharmacology 1981;20:839–43. https://doi.org/10.1016/0028-3908(81)90076-9.Search in Google Scholar PubMed

11. Scheline, Ronald R. Handbook of mammalian metabolism of plant compounds. Boca Raton, FL, USA: CRC Press; 2017.10.1201/9780203712504Search in Google Scholar

12. Tseng, YL, Shieh, M-H, Kuo, F-H. Metabolites of ephedrines in human urine after administration of a single therapeutic dose. Forensic Sci Int 2006;157:149–55. https://doi.org/10.1016/j.forsciint.2005.04.008.Search in Google Scholar PubMed

13. Pokrajac, M, Miljković, B, Bisailović, B. Mass spectrometric investigation of 2-aminopropiophenones and some of their metabolites. Rapid Commun Mass Spectrom 1991;5:59–61. https://doi.org/10.1002/rcm.1290050202.Search in Google Scholar PubMed

14. Corkery, JM, Schifano, F, Oyefeso, A, Ghodse, AH, Tonia, T, Naidoo, V, et al.. Overview of literature and information on “khat-related” mortality: a call for recognition of the issue and further research. Ann Istituto Super Sanita 2011;47:445–64. https://doi.org/10.4415/ANN_11_04_17.Search in Google Scholar PubMed

15. Ageely, HM, El-Nagar, MM, Abouelmagd, A, Abou-Elhamd, AS, Kelany, ME, Patil, BR. Khat extract mediated morphological and histochemical alterations in rat liver. Int J Adv Res 2014;2:971–80.Search in Google Scholar

16. Alsalahi, A, Abdulla, MA, Al-Mamary, M, Noordin, MI, Abdelwahab, SI, Alabsi, AM, et al.. Toxicological features of Catha edulis (Khat) on livers and kidneys of male and female Sprague-Dawley rats: a subchronic study. Evid Base Compl Alternative Med 2012;2012:829401. https://doi.org/10.1155/2012/829401.Search in Google Scholar PubMed PubMed Central

17. Al-hebshi, N, Al-haroni, M, Skaug, N. In vitro antimicrobial and resistance-modifying activities of aqueous crude khat extracts against oral microorganisms. Arch Oral Biol 2006;51:183–8. https://doi.org/10.1016/j.archoralbio.2005.08.001.Search in Google Scholar PubMed

18. Alamir, A, Watterson, J, Attafi, I. Development and validation of a Uplc-Qtof-Ms method for blood analysis of isomeric amphetamine-related drugs. Separations 2022;9:285. https://doi.org/10.3390/separations9100285.Search in Google Scholar

19. Negri, P, Cabrices, O, Fritch, D, Stauffer, M, Koenig, N, Shollenberger, D, et al.. Streamlined undnown screening for postmortem analysis. Framingham, MA, USA: AB Sciex; 2019. https://lcms.cz/labrulez-bucket-strapi-h3hsga3/Streamlined_Unknown_Screening_for_Postmortem_Analysis_fc05534354/Streamlined-Unknown-Screening-for-Postmortem-Analysis.pdf [Accessed 28 September 2022].Search in Google Scholar

20. Brenneisen, R, Mathys, K, Geisshüsler, S, Fisch, H, Koelbing, U, Kalix, P. Determination of S-(-)-cathinone and its main metabolite R, S-(-)-norephedrine in human plasma by high-performance liquid chromatography and photodiode array detection. J Liq Chromatogr 1991;14:271–86. https://doi.org/10.1080/01483919108049614.Search in Google Scholar

21. Widler, P, Mathys, K, Brenneisen, R, Kalix, P, Fisch, HU. Pharmacodynamics and pharmacokinetics of khat: a controlled study. Clin Pharmacol Ther 1994;55:556–62. https://doi.org/10.1038/clpt.1994.69.Search in Google Scholar PubMed

22. Al Suwaidi, J, Ali, WM, Aleryani, SL. Cardiovascular complications of Khat. Clin Chim Acta 2013;419:11–4. https://doi.org/10.1016/j.cca.2013.01.007.Search in Google Scholar PubMed

23. Bede, P, El-Kininy, N, O’Hara, F, Menon, P, Finegan, E, Healy, D. ‘Khatatonia’–cathinone-induced hypertensive encephalopathy. Neth J Med 2017;75:448–50.Search in Google Scholar

24. Oyungu, E, Kioy, P, Patel, N. Effect of Catha edulis (khat) on behaviour and its potential to induce seizures in Sprague Dawley rats. East Afr Med J 2007;84:219–25. https://doi.org/10.4314/eamj.v84i5.9529.Search in Google Scholar PubMed

25. Toennes, SW, Kauert, GF. Driving under the influence of khat—alkaloid concentrations and observations in forensic cases. Forensic Sci Int 2004;140:85–90. https://doi.org/10.1016/j.forsciint.2003.11.028.Search in Google Scholar PubMed

26. Ali, WM, Zubaid, M, Al-Motarreb, A, Singh, R, Al-Shereiqi, SZ, Shehab, A, et al.. Association of khat chewing with increased risk of stroke and death in patients presenting with acute coronary syndrome. Mayo Clin. Proc. 2010;85:974–80. https://doi.org/10.4065%2Fmcp.2010.0398.10.4065/mcp.2010.0398Search in Google Scholar PubMed PubMed Central

27. Corkery, JM, Schifano, F, Oyefeso, A, Ghodse, AH, Tonia, T, Naidoo, V, et al.. ‘Bundle of fun’ or ‘bunch of problems’? Case series of khat-related deaths in the UK. Drugs: Educ, Prev Pol 2011;18:408–25. https://doi.org/10.3109/09687637.2010.504200.Search in Google Scholar

28. Thiel, A, Dressler, D. Dyskinesias possibly induced by norpseudoephedrine. J Neurol 1994;241:167–9. https://doi.org/10.1007/bf00868344.Search in Google Scholar

29. Belhadj-Tahar, H, Sadeg, N. Methcathinone: a new postindustrial drug. Forensic Sci Int 2005;153:99–101. https://doi.org/10.1016/j.forsciint.2005.04.023.Search in Google Scholar PubMed

30. Vignali, C, Moretti, M, Groppi, A, Osculati, AMM, Tajana, L, Morini, L. Distribution of the synthetic cathinone α-pyrrolidinohexiophenone in biological specimens. J Anal Toxicol 2019;43:e1–6. https://doi.org/10.1093/jat/bky047.Search in Google Scholar PubMed

31. Woldeamanuel, GG, Geta, TG. Impact of chronic Khat (Catha edulis Forsk) chewing on pulmonary function test and oxygen saturation in humans: a comparative study. SAGE Open Med 2019;7:2050312118824616. https://doi.org/10.1177/2050312118824616.Search in Google Scholar PubMed PubMed Central

32. Al-Mamary, M, Al-Habori, M, Al-Aghbari, A, Baker, M. Investigation into the toxicological effects of Catha edulis leaves: a short term study in animals. Phytother Res Int J Devoted Pharmacol Toxicol Eval Nat Product Deriv 2002;16:127–32. https://doi.org/10.1002/ptr.835.Search in Google Scholar PubMed

33. Yitna, E, Mossie, A, Yami, A. Effects of Khat (Catha edulis) on bronchial asthma. Open J Asthma 2018;2:005–10. https://doi.org/10.17352/oja.000008.Search in Google Scholar

34. Kalix, P. Effect of the alkaloid (–)-cathinone on the release of radioactivity from rat striatal tissue prelabelled with 3H-serotonin. Neuropsychobiology 1984;12:127–9. https://doi.org/10.1159/000118124.Search in Google Scholar PubMed

35. Gygi, MP, Fleckenstein, AE, Gibb, JW, Hanson, GR. Role of endogenous dopamine in the neurochemical deficits induced by methcathinone. J Pharmacol Exp Therapeut 1997;283:1350–5.Search in Google Scholar

36. Fleckenstein, AE, Haughey, HM, Metzger, RR, Kokoshka, JM, Riddle, EL, Hanson, JE, et al.. Differential effects of psychostimulants and related agents on dopaminergic and serotonergic transporter function. Eur J Pharmacol 1999;382:45–9. https://doi.org/10.1016/s0014-2999(99)00588-9.Search in Google Scholar PubMed

37. Critchlow, S, Seifert, R. Khat-induced paranoid psychosis. Br J Psychiatr 1987;150:247–9. https://doi.org/10.1192/bjp.150.2.247.Search in Google Scholar PubMed

38. Hassan, NA, Gunaid, AA, El-Khally, FM, Murray-Lyon, IM. The effect of chewing Khat leaves on human mood. Neurosci J 2002;7:184–7.Search in Google Scholar

39. Mohan, S, Abdelwahab, SI, Hobani, YH, Syam, S, Al-Zubairi, AS, Al-Sanousi, R, et al.. Catha edulis extract induces H9c2 cell apoptosis by increasing reactive oxygen species generation and activation of mitochondrial proteins. Phcog Mag 2016;12(3 Suppl):S321. https://doi.org/10.4103/0973-1296.185732.Search in Google Scholar PubMed PubMed Central

Received: 2022-07-17

Accepted: 2022-12-12

Published Online: 2023-03-09

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https://doi.org/10.1515/dmpt-2022-0154

Keywords for this article

Catha edulis; cathine; cathinone; disposition; HPLC-IT/MS; kinetics; UPLC-QTOF/MS