Elizabeth A Maxwell1, Tamara I King2, Shyam H Kamble2,3, Kanumuri Siva Rama Raju2,3, Erin C Berthold2, Francisco León4, Aidan Hampson5, Lance R McMahon6, Christopher R McCurdy7,8,9, Abhisheak Sharma10,11. 1. Department of Small Animal Clinical Sciences, College of Veterinary Medicine, University of Florida, Gainesville, FL, USA. 2. Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, FL, USA. 3. Translational Drug Development Core, Clinical and Translational Science Institute, University of Florida, Gainesville, FL, USA. 4. Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, FL, USA. 5. Division of Therapeutics and Medical Consequences, National Institute on Drug Abuse, National Institutes of Health, Bethesda, MD, USA. 6. Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, FL, USA. 7. Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, FL, USA. cmccurdy@cop.ufl.edu. 8. Translational Drug Development Core, Clinical and Translational Science Institute, University of Florida, Gainesville, FL, USA. cmccurdy@cop.ufl.edu. 9. Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, FL, USA. cmccurdy@cop.ufl.edu. 10. Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, FL, USA. asharma1@cop.ufl.edu. 11. Translational Drug Development Core, Clinical and Translational Science Institute, University of Florida, Gainesville, FL, USA. asharma1@cop.ufl.edu.
Abstract
BACKGROUND AND OBJECTIVES: 7-Hydroxymitragynine (7-HMG) is an oxidative metabolite of mitragynine, the most abundant alkaloid in the leaves of Mitragyna speciosa (otherwise known as kratom). While mitragynine is a weak partial µ-opioid receptor (MOR) agonist, 7-HMG is a potent and full MOR agonist. It is produced from mitragynine by cytochrome P450 (CYP) 3A, a drug-metabolizing CYP isoform predominate in the liver that is also highly expressed in the intestine. Given the opioidergic potency of 7-HMG, a single oral dose pharmacokinetic and safety study of 7-HMG was performed in beagle dogs. METHODS: Following a single oral dose (1 mg/kg) of 7-HMG, plasma samples were obtained from healthy female beagle dogs. Concentrations of 7-HMG were determined using ultra-performance liquid chromatography coupled with a tandem mass spectrometer (UPLC-MS/MS). Pharmacokinetic parameters were calculated using a model-independent non-compartmental analysis of plasma concentration-time data. RESULTS: Absorption of 7-HMG was rapid, with a peak plasma concentration (Cmax, 56.4 ± 1.6 ng/ml) observed within 15 min post-dose. In contrast, 7-HMG elimination was slow, exhibiting a mono-exponential distribution and mean elimination half-life of 3.6 ± 0.5 h. Oral dosing of 1 mg/kg 7-HMG was well tolerated with no observed adverse events or significant changes to clinical laboratory tests. CONCLUSIONS: These results provide the first pharmacokinetic and safety data for 7-HMG in the dog and therefore contribute to the understanding of the putative pharmacologic role of 7-HMG resulting from an oral delivery of mitragynine from kratom.
BACKGROUND AND OBJECTIVES: 7-Hydroxymitragynine (7-HMG) is an oxidative metabolite of mitragynine, the most abundant alkaloid in the leaves of Mitragyna speciosa (otherwise known as kratom). While mitragynine is a weak partial µ-opioid receptor (MOR) agonist, 7-HMG is a potent and full MOR agonist. It is produced from mitragynine by cytochrome P450 (CYP) 3A, a drug-metabolizing CYP isoform predominate in the liver that is also highly expressed in the intestine. Given the opioidergic potency of 7-HMG, a single oral dose pharmacokinetic and safety study of 7-HMG was performed in beagle dogs. METHODS: Following a single oral dose (1 mg/kg) of 7-HMG, plasma samples were obtained from healthy female beagle dogs. Concentrations of 7-HMG were determined using ultra-performance liquid chromatography coupled with a tandem mass spectrometer (UPLC-MS/MS). Pharmacokinetic parameters were calculated using a model-independent non-compartmental analysis of plasma concentration-time data. RESULTS: Absorption of 7-HMG was rapid, with a peak plasma concentration (Cmax, 56.4 ± 1.6 ng/ml) observed within 15 min post-dose. In contrast, 7-HMG elimination was slow, exhibiting a mono-exponential distribution and mean elimination half-life of 3.6 ± 0.5 h. Oral dosing of 1 mg/kg 7-HMG was well tolerated with no observed adverse events or significant changes to clinical laboratory tests. CONCLUSIONS: These results provide the first pharmacokinetic and safety data for 7-HMG in the dog and therefore contribute to the understanding of the putative pharmacologic role of 7-HMG resulting from an oral delivery of mitragynine from kratom.
Authors: Alicia G Lydecker; Abhisheak Sharma; Christopher R McCurdy; Bonnie A Avery; Kavita M Babu; Edward W Boyer Journal: J Med Toxicol Date: 2016-10-17
Authors: Erin C Berthold; Shyam H Kamble; Kanumuri S Raju; Michelle A Kuntz; Alexandria S Senetra; Marco Mottinelli; Francisco León; Luis F Restrepo; Avi Patel; Nicholas P Ho; Takato Hiranita; Abhisheak Sharma; Lance R McMahon; Christopher R McCurdy Journal: Drug Metab Dispos Date: 2021-11-10 Impact factor: 3.922
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