University of Florida Gainesville, Florida, United States
Purpose: Mitragyna speciosa (kratom) is a tree native to Southeast Asia that has been used traditionally to treat pain or to increase energy. Kratom is now being investigated for its potential therapeutic applications in the clinic1. As it is a complex natural product, the individual alkaloids need to be studied. Mitraciliatine is a minor alkaloid found in kratom that is of particular interest due to it being a stereoisomer of the most abundant alkaloid, mitragynine. Recently, a clinical pharmacokinetic (PK) assessment of kratom was performed in humans and found that mitraciliatine had the high systemic exposure per mg administered compared to the other studied alkaloids, including mitragynine2. A PK evaluation of mitraciliatine was conducted in Sprague Dawley rats to better understand the exposure of this alkaloid and how it may contribute to the pharmacology of complex kratom products. Methods: A pharmacokinetic study in male Sprague Dawley rats was conducted. Mitraciliatine was administered as 2 mg/kg intravenous (I.V.) or 5 mg/kg oral (P.O.) and blood samples were taken pre-dose, 0.08, 0.17, 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 8, 12, 18, and 24 hours. The plasma was separated and analyzed via an ultra-performance liquid chromatography tandem mass spectrometry method that was validated to quantify mitraciliatine. A noncompartmental analysis was performed using Phoenix WinNonlin (version 8.4.3) to obtain the pharmacokinetic parameters. Results: Mitraciliatine has a volume of distribution of 27.6 ± 1.6 L/kg (I.V.), a clearance of 2.6 ± 0.6 L/h/kg and an absolute oral bioavailability of 6.7%. Analytes were detected in the mass transitions of presumptive metabolites formed by O-demethylation and oxidation of mitraciliatine. Conclusion: Compared to mitragynine, mitraciliatine has a higher clearance and lower systemic exposure. Mitraciliatine also has a much lower absolute oral bioavailability (6.7% vs 17%)3. Mitragynine has two other stereoisomers, speciocilitine (SPC) and speciogynine (SPG). SPC has a similar bioavailability to mitragynine (20.7%) but SPG has a bioavailability similar to mitraciliatine (4.1%). Mitraciliatine has a higher clearance when compared to SPC (0.7 ± 0.2 L/hr/kg) but a similar clearance when compared to SPG (3.3 ± 0.1 L/hr/kg)4. The mitraciliatine results explained here will help to better understand the overall pharmacokinetics of kratom.
References: 1. 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. Neuropharmacology. 2018;134:108-120. doi:10.1016/j.neuropharm.2017.08.026 2. Tanna RS, Nguyen JT, Hadi DL, et al. Clinical Pharmacokinetic Assessment of Kratom (Mitragyna speciosa), a Botanical Product with Opioid-like Effects, in Healthy Adult Participants. Pharmaceutics. 2022;14(3):620. doi:10.3390/pharmaceutics14030620 3. Avery BA, Boddu SP, Sharma A, et al. Comparative Pharmacokinetics of Mitragynine after Oral Administration of Mitragyna speciosa (Kratom) Leaf Extracts in Rats. Planta Med. 2019;85(4):340-346. doi:10.1055/a-0770-3683 4. Berthold EC, Kamble SH, Raju KS, et al. Preclinical pharmacokinetic study of speciociliatine, a kratom alkaloid, in rats using an UPLC-MS/MS method. J Pharm Biomed Anal. 2021;194:113778. doi:10.1016/j.jpba.2020.113778
