RSS-Feed abonnieren
DOI: 10.1055/a-1212-5475
Pharmacokinetics and Safety of Mitragynine in Beagle Dogs
Gefördert durch: National Institute on Drug Abuse R01 DA047855Gefördert durch: National Institute on Drug Abuse UG3 DA048353
Gefördert durch: National Center for Advancing Translational Sciences UL1TR001427
Abstract
Mitragynine is the most abundant psychoactive alkaloid derived from the leaves of Mitragyna speciosa (kratom), a tropical plant indigenous to regions of Southeast Asia. Mitragynine displays a moderate affinity to opioid receptors, and kratom is often self-prescribed to treat pain and/or opioid addiction. The purpose of this study was to investigate the safety and pharmacokinetic properties of mitragynine in the dog. Single dose oral (5 mg/kg) and intravenous (0.1 mg/kg) pharmacokinetic studies of mitragynine were performed in female beagle dogs. The plasma concentrations of mitragynine were measured using ultra-performance liquid chromatography coupled with a tandem mass spectrometer, and the pharmacokinetic properties were analyzed using non-compartmental analysis. Following intravenous administration, mitragynine showed a large volume of distribution (Vd, 6.3 ± 0.6 L/kg) and high clearance (Cl, 1.8 ± 0.4 L/h/kg). Following oral mitragynine dosing, first peak plasma (Cmax, 278.0 ± 47.4 ng/mL) concentrations were observed within 0.5 h. A potent mu-opioid receptor agonist and active metabolite of mitragynine, 7-hydroxymitragynine, was also observed with a Cmax of 31.5 ± 3.3 ng/mL and a Tmax of 1.7 ± 0.6 h in orally dosed dogs while its plasma concentrations were below the lower limit of quantification (1 ng/mL) for the intravenous study. The absolute oral bioavailability of mitragynine was 69.6%. Administration of mitragynine was well tolerated, although mild sedation and anxiolytic effects were observed. These results provide the first detailed pharmacokinetic information for mitragynine in a non-rodent species (the dog) and therefore also provide significant information for allometric scaling and dose predictions when designing clinical studies.
Key words
mitragynine - 7-hydroxymitragynine - absolute bioavailability - pharmacokinetics - kratom - Mitragyna speciosa - RubiaceaeSupporting Information
- Supporting Information
Isolation of mitragynine, synthesis of 7-hydroxymitragynine, 1H NMR, 13C NMR, 2D HSQC, and UHPLC-PDA-Q-TOF spectrometric analysis, representative chromatograms of mitragynine and 7-hydroxymitragynine, and concentration-time profiles for the oral study are available as Supporting Information.
Publikationsverlauf
Eingereicht: 31. März 2020
Angenommen nach Revision: 29. Juni 2020
Artikel online veröffentlicht:
21. Juli 2020
© 2020. Thieme. All rights reserved.
Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany
-
References
- 1 Adkins JE, Boyer EW, McCurdy CR. Mitragyna speciosa, a psychoactive tree from Southeast Asia with opioid activity. Curr Top Med Chem 2011; 11: 1165-1175
- 2 Jansen KL, Prast CJ. Ethnopharmacology of kratom and the Mitragyna alkaloids. J Ethnopharmacol 1988; 23: 115-119
- 3 Prozialeck WC, Avery BA, Boyer EW, Grundmann O, Henningfield JE, Kruegel AC, McMahon LR, McCurdy CR, Swogger MT, Veltri CA, Singh D. Kratom policy: The challenge of balancing therapeutic potential with public safety. Int J Drug Policy 2019; 70: 70-77
- 4 Takayama H. Chemistry and pharmacology of analgesic indole alkaloids from the rubiaceous plant, Mitragyna speciosa . Chem Pharm Bull 2004; 52: 916-928
- 5 Hazim AI, Ramanathan S, Parthasarathy S, Muzaimi M, Mansor SM. Anxiolytic-like effects of mitragynine in the open-field and elevated plus-maze tests in rats. J Physiol Sci 2014; 64: 161-169
- 6 Mossadeq WS, Sulaiman M, Mohamad TT, Chiong H, Zakaria Z, Jabit M, Baharuldin M, Israf D. Anti-inflammatory and antinociceptive effects of Mitragyna speciosa Korth methanolic extract. Med Princ Pract 2009; 18: 378-384
- 7 Idayu NF, Hidayat MT, Moklas M, Sharida F, Raudzah AN, Shamima A, Apryani E. Antidepressant-like effect of mitragynine isolated from Mitragyna speciosa Korth in mice model of depression. Phytomedicine 2011; 18: 402-407
- 8 McWhirter L, Morris S. A case report of inpatient detoxification after kratom (Mitragyna speciosa) dependence. Eur Addict Res 2010; 16: 229-231
- 9 Macko E, Weisbach J, Douglas B. Some observations on the pharmacology of mitragynine. Arch Int Pharmacodyn Ther 1972; 198: 145
- 10 Prozialeck WC, Jivan JK, Andurkar SV. Pharmacology of kratom: an emerging botanical agent with stimulant, analgesic and opioid-like effects. J Am Osteopath Assoc 2012; 112: 792-799
- 11 Obeng S, Kamble SH, Reeves ME, Restrepo LF, Patel A, Behnke M, Chear N, Ramanathan S, Sharma A, Leon F. Investigation of the adrenergic and opioid binding affinities, metabolic stability, plasma protein binding properties and functional effects of selected indole-based kratom alkaloids. J Med Chem 2020; 63: 433-439
- 12 Váradi A, Marrone GF, Palmer TC, Narayan A, Szabó MR, Le Rouzic V, Grinnell SG, Subrath JJ, Warner E, Kalra S. Mitragynine/corynantheidine pseudoindoxyls as opioid analgesics with mu agonism and delta antagonism, which do not recruit β-arrestin-2. J Med Chem 2016; 59: 8381-8397
- 13 Madariaga-Mazon A, Marmolejo-Valencia AF, Li Y, Toll L, Houghten RA, Martinez-Mayorga K. Mu-Opioid receptor biased ligands: A safer and painless discovery of analgesics?. Drug Discov Today 2017; 22: 1719-1729
- 14 Food and Drug Administration. FDA and Kratom. Available at (Accessed March 31, 2020): https://www.fda.gov/news-events/public-health-focus/fda-and-kratom
- 15 Yue K, Kopajtic TA, Katz JL. Abuse liability of mitragynine assessed with a self-administration procedure in rats. Psychopharmacol 2018; 235: 2823-2829
- 16 Hemby SE, McIntosh S, Leon F, Cutler SJ, McCurdy CR. Abuse liability and therapeutic potential of the Mitragyna speciosa (kratom) alkaloids mitragynine and 7-hydroxymitragynine. Addict Biol 2019; 24: 874-885
- 17 Singh D, Muller CP, Vicknasingam BK. Kratom (Mitragyna speciosa) dependence, withdrawal symptoms and craving in regular users. Drug Alcohol Depend 2014; 139: 132-137
- 18 Singh D, Muller CP, Vicknasingam BK, Mansor SM. Social functioning of kratom (Mitragyna speciosa) users in Malaysia. J Psychoactive Drugs 2015; 47: 125-131
- 19 Singh D, Yeou Chear NJ, Narayanan S, Leon F, Sharma A, McCurdy CR, Avery BA, Balasingam V. Patterns and reasons for kratom (Mitragyna speciosa) use among current and former opioid poly-drug users. J Ethnopharmacol 2020; 249: 112462
- 20 Ya K, Tangamornsuksan W, Scholfield CN, Methaneethorn J, Lohitnavy M. Pharmacokinetics of mitragynine, a major analgesic alkaloid in kratom (Mitragyna speciosa): A systematic review. Asian J Psychiatr 2019; 43: 73-82
- 21 Trakulsrichai S, Sathirakul K, Auparakkitanon S, Krongvorakul J, Sueajai J, Noumjad N, Sukasem C, Wananukul W. Pharmacokinetics of mitragynine in man. Drug Des Devel Ther 2015; 9: 2421
- 22 Food and Drug Administration. Guidance for industry: estimating the maximum safe starting dose in initial clinical trials for therapeutics in adult healthy volunteers. Available at (Accessed March 31, 2020): https://www.fda.gov/regulatory-information/search-fda-guidance-documents/estimating-maximum-safe-starting-dose-initial-clinical-trials-therapeutics-adult-healthy-volunteers
- 23 Nair A, Morsy MA, Jacob S. Dose translation between laboratory animals and human in preclinical and clinical phases of drug development. Drug Develop Res 2018; 79: 373-382
- 24 Food and Drug Administration. Product development under the animal rule: guidance for industry. Available at (Accessed March 31, 2020): https://www.fda.gov/media/88625/download
- 25 Kruegel AC, Uprety R, Grinnell SG, Langreck C, Pekarskaya EA, Le Rouzic V, Ansonoff M, Gassaway MM, Pintar JE, Pasternak GW, Javitch JA, Majumdar S, Sames D. 7-Hydroxymitragynine is an active metabolite of mitragynine and a key mediator of its analgesic effects. ACS Cent Sci 2019; 5: 992-1001
- 26 Food and Drug Administration. Bioanalytical method validation guidance for industry. Available at (Accessed March 31, 2020): https://www.fda.gov/regulatory-information/search-fda-guidance-documents/bioanalytical-method-validation-guidance-industry
- 27 Avery BA, Boddu SP, Sharma A, Furr EB, Leon F, Cutler SJ, McCurdy CR. Comparative pharmacokinetics of mitragynine after oral administration of Mitragyna speciosa (Kratom) leaf extracts in rats. Planta Med 2019; 85: 340-346
- 28 ChemAxon. Marvin 17.14.0. Available at (Accessed March 31, 2020): https://www.chemaxon.com
- 29 Gilor S, Gilor C. Common laboratory artifacts caused by inappropriate sample collection and transport: how to get the most out of a sample. Top Companion Anim Med 2011; 26: 109-118
- 30 Casale TB, Bowman S, Kaliner M. Induction of human cutaneous mast cell degranulation by opiates and endogenous opioid peptides: evidence for opiate and nonopiate receptor participation. J Allergy Clin Immunol 1984; 73: 775-781
- 31 Saljoughian M. Opioids: allergy vs. pseudoallergy. US Pharm 2006; 7: HS-5-HS-9
- 32 Ennis M, Schneider C, Nehring E, Lorenz W. Histamine release induced by opioid analgesics: a comparative study using porcine mast cells. Agents Actions 1991; 33: 20-22
- 33 Kruegel AC, Grundmann O. The medicinal chemistry and neuropharmacology of kratom: A preliminary discussion of a promising medicinal plant and analysis of its potential for abuse. Neuropharmacol 2018; 134: 108-120
- 34 Jaiswal S, Shukla M, Sharma A, Rangaraj N, Vaghasiya K, Malik MY, Lal J. Preclinical pharmacokinetics and ADME characterization of a novel anticancer chalcone, cardamonin. Drug Test Anal 2017; 9: 1124-1136
- 35 Godfrey KR, Arundel PA, Dong Z, Bryant R. Modelling the double peak phenomenon in pharmacokinetics. Comput Methods Programs Biomed 2011; 104: 62-69
- 36 Kamble SH, Sharma A, King TI, León F, McCurdy CR, Avery BA. Metabolite profiling and identification of enzymes responsible for the metabolism of mitragynine, the major alkaloid of Mitragyna speciosa (kratom). Xenobiotica 2019; 49: 1279-1288
- 37 Kulkarni KH, Yang Z, Niu T, Hu M. Effects of estrogen and estrus cycle on pharmacokinetics, absorption, and disposition of genistein in female Sprague-Dawley rats. J Agric Food Chem 2012; 60: 7949-7956
- 38 Martinez SE, Shi J, Zhu HJ, Jimenez TEP, Zhu Z. Absolute quantitation of drug-metabolizing cytochrome p450 enzymes and accessory proteins in dog liver microsomes using label-free standard-free analysis reveals interbreed variability. Drug Metab Dispos 2019; 47: 1314-1324
- 39 Nishibe Y, Wakabayashi M, Harauchi T, Ohno K. Characterization of cytochrome P450 (CYP3A12) induction by rifampicin in dog liver. Xenobiotica 1998; 28: 549-557
- 40 Court MH. Canine cytochrome P450 (CYP) pharmacogenetics. Vet Clin North Am Small Anim Pract 2013; 43: 1027
- 41 Martignoni M, Groothuis GM, de Kanter R. Species differences between mouse, rat, dog, monkey and human CYP-mediated drug metabolism, inhibition and induction. Expert Opin Drug Metab Toxicol 2006; 2: 875-894
- 42 Pasanen M. Species Differences in CYP Enzymes. In: Angosto MC, Gomez-Lechon MJ. eds. Citocromo P450. Madrid: Instituto De Espana, Real Academia Nacional De Farmacia Madrid; 2004: 3-90
- 43 Sharma A, Kamble SH, Leon F, Chear NJ, King TI, Berthold EC, Ramanathan S, McCurdy CR, Avery BA. Simultaneous quantification of ten key Kratom alkaloids in Mitragyna speciosa leaf extracts and commercial products by ultra-performance liquid chromatography-tandem mass spectrometry. Drug Test Anal 2019; 11: 1162-1171
- 44 Veterinary cooperative oncology group – common terminology criteria for adverse events (VCOG-CTCAE) following chemotherapy or biological antineoplastic therapy in dogs and cats v1.1. Vet Comp Oncol 2016; 14: 417-446