2. Academic Validation
  3. Metabolism of Speciociliatine, an Overlooked Kratom Alkaloid for its Potential Pharmacological Effects

Metabolism of Speciociliatine, an Overlooked Kratom Alkaloid for its Potential Pharmacological Effects

  • AAPS J. 2022 Jul 19;24(5):86. doi: 10.1208/s12248-022-00736-8.
Shyam H Kamble 1 2 3,  Erin C Berthold 1,  Siva Rama Raju Kanumuri 1 2,  Tamara I King 1 2,  Michelle A Kuntz 1 2,  Francisco León 4 5,  Marco Mottinelli 4 6,  Lance R McMahon 7,  Christopher R McCurdy 8 9 10,  Abhisheak Sharma 11 12
Affiliations

Affiliations

  • 1 Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, FL, 32610, USA.
  • 2 Translational Drug Development Core, Clinical and Translational Sciences Institute, University of Florida, Gainesville, FL, 32610, USA.
  • 3 Agios Pharmaceuticals, Inc., 88 Sidney Street, Cambridge, MA, 02139, USA.
  • 4 Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, FL, 32610, USA.
  • 5 Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Columbia, SC, 29208, USA.
  • 6 Laboratory for Neglected Disease Drug Discovery, College of Science, Department of Chemistry and Chemical Biology, Northeastern University, 360 Huntington Ave, Boston, MA, 02115, USA.
  • 7 Texas Tech University Health Sciences Center, Lubbock, TX, 79409, USA.
  • 8 Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, FL, 32610, USA. [email protected].
  • 9 Translational Drug Development Core, Clinical and Translational Sciences Institute, University of Florida, Gainesville, FL, 32610, USA. [email protected].
  • 10 Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, FL, 32610, USA. [email protected].
  • 11 Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, FL, 32610, USA. [email protected].
  • 12 Translational Drug Development Core, Clinical and Translational Sciences Institute, University of Florida, Gainesville, FL, 32610, USA. [email protected].
PMID: 35854066 DOI: 10.1208/s12248-022-00736-8
Abstract

Speciociliatine, a diastereomer of mitragynine, is an indole-based alkaloid found in kratom (Mitragyna speciosa). Kratom has been widely used for the mitigation of pain and opioid dependence, as a mood enhancer, and/or as an energy booster. Speciociliatine is a partial µ-opioid agonist with a 3-fold higher binding affinity than mitragynine. Speciociliatine has been found to be a major circulating alkaloid in humans following oral administration of a kratom product. In this report, we have characterized the metabolism of speciociliatine in human and preclinical species (mouse, rat, dog, and cynomolgus monkey) liver microsomes and hepatocytes. Speciociliatine metabolized rapidly in monkey, rat, and mouse hepatocytes (in vitro half-life was 6.6 ± 0.2, 8.3 ± 1.1, 11.2 ± 0.7 min, respectively), while a slower metabolism was observed in human and dog hepatocytes (91.7 ± 12.8 and > 120 min, respectively). Speciociliatine underwent extensive metabolism, primarily through monooxidation and O-demethylation metabolic pathways in liver microsomes and hepatocytes across species. No human-specific or disproportionate metabolites of speciociliatine were found in human liver microsomes. The metabolism of speciociliatine was predominantly mediated by CYP3A4 with minor contributions by CYP2D6.

Keywords

Cytochrome P450; Hepatocytes; Kratom; LC–MS/MS; Liver microsomes; Metabolism; Speciociliatine.

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