University of Florida Alachua, Florida, United States
Purpose: Kratom (Mitragyna speciosa) is a tropical evergreen tree from Southeast Asia that produces opioid- and stimulant-like effects1. It is used as a self-treatment for pain, and as an energy booster. Mitragynine, is a major alkaloid in kratom, and is thought to be primarily responsible for the pharmacological effects of kratom1,2. An oral multiple-dose pharmacokinetic study of mitragynine was firstly performed to describe the steady-state pharmacokinetics of mitragynine. Methods: Multiple-dose pharmacokinetic studies of low (10 mg/kg q12h) and high (40 mg/kg q12h) oral doses of mitragynine were conducted. On day 5, after the last (9th) dose, rats were connected to an automated blood sampling system. Blood samples were collected at pre-dose, 96.08, 96.17, 96.25, 96.5, 96.75, 97, 98, 100, 104, 108, 114, 120, 132, and 144 hours post-dose. Plasma was separated from whole blood and plasma concentration of mitragynine and its metabolites (7-hydroxymitragynine, mitragynine pseudoindoxyl, 9-hydroxycorynantheidine, and mitragynine acid) were determined using ultra-performance liquid chromatography-tandem mass spectrometry3. Pre-study (0 hr) and 96 hr blood samples from the high dose mitragynine study were also analyzed for clinical chemistry and hematological tests. The pharmacokinetic parameters were obtained by non-compartmental analysis using Phoenix WinNonlin, version 6.4. Results: There were no abnormal hematological findings for the high-dose mitragynine study. The fold-changes between low and high-dose mitragynine for Cavg, AUCall, and AUC0-inf were 0.7, 0.9, and 0.9 respectively. The accumulation indices were 1.5-2.0 in both groups. The accumulation index indicated that mitragynine has a weak accumulation, and the results of fluctuation (%) can be seen as a reference to determine the dosing interval in the future. And the fluctuations were 248.4% and 146.2% in low and high doses, respectively. The ratios between each metabolite area under the curve (AUC) of plasma concentration-time profile and mitragynine AUC of plasma concentration-time profile were 55.1 ± 8.9% for mitragynine acid, 37.4 ± 6.1% for 9-hydroxycorynantheidine, 5.0 ± 1.0% for 7- hydroxymitragynine, and 1.0 ± 0 % for mitragynine pseudoindoxyl. Conclusion: This study establishes the steady-state pharmacokinetic profile of mitragynine after low and high oral doses. The major metabolites of mitragynine in rats were mitragynine acid and 9-hydroxycorynantheidine while 7-hydroxymitragynine and mitragynine pseudoindoxyl were found to be minor metabolites with metabolite to parent ratios < 10%. The pharmacokinetic results indicated that mitragynine has dose linearity which is a preferable property for new drug development as it helps facilitate dose regimens and dose adjustments. Furthermore, the clinical chemistry and hematological tests showed the safety of high-dose mitragynine and provided preliminary results for further toxicokinetic studies. References: 1. Avery, B. A.; Boddu, S. P.; Sharma, A.; Furr, E. B.; Leon, F.; Cutler, S. J.; McCurdy, C. R., Comparative pharmacokinetics of mitragynine after oral administration of Mitragyna speciosa (Kratom) leaf extracts in rats. Planta medica 2019, 85 (04), 340-346. 2. Maxwell, E. A.; King, T. I.; Kamble, S. H.; Raju, K. S. R.; Berthold, E. C.; León, F.; Avery, B. A.; McMahon, L. R.; McCurdy, C. R.; Sharma, A., Pharmacokinetics and safety of mitragynine in beagle dogs. Planta medica 2020, 86 (17), 1278-1285. 3. Food and Drug Administration, Guidance for industry: bioanalytical method validation. Rockville, MD, USA: US Department of Health and Human Services, US FDA. Center for Drug Evaluation and Research 2018.
