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

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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.

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Funding

This study was supported by R01 DA047855 and UG3/UH3 DA048353 grants from the National Institute on Drug Abuse and the University of Florida Clinical and Translational Science Institute, which is supported in part by the NIH National Center for Advancing Translational Sciences under award number UL1TR001427.

Author information

Author notes

  1. Shyam H. Kamble

    Present address: Agios Pharmaceuticals, Inc., 88 Sidney Street, Cambridge, MA, 02139, USA

  2. Francisco León

    Present address: Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Columbia, SC, 29208, USA

  3. Marco Mottinelli

    Present address: Laboratory for Neglected Disease Drug Discovery, College of Science, Department of Chemistry and Chemical Biology, Northeastern University, 360 Huntington Ave, Boston, MA, 02115, USA

Authors and Affiliations

  1. Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, FL, 32610, USA

    Shyam H. Kamble, Erin C. Berthold, Siva Rama Raju Kanumuri, Tamara I. King, Michelle A. Kuntz, Christopher R. McCurdy & Abhisheak Sharma

  2. Translational Drug Development Core, Clinical and Translational Sciences Institute, University of Florida, Gainesville, FL, 32610, USA

    Shyam H. Kamble, Siva Rama Raju Kanumuri, Tamara I. King, Michelle A. Kuntz, Christopher R. McCurdy & Abhisheak Sharma

  3. Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, FL, 32610, USA

    Francisco León, Marco Mottinelli & Christopher R. McCurdy

  4. Texas Tech University Health Sciences Center, Lubbock, TX, 79409, USA

    Lance R. McMahon

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Contributions

SK, EB, KSRR, TK, MK: conceptualization, methodology, investigation, data curation, writing — original draft, preparation. MM, FL: methodology, investigation, writing — review & editing. LM, CRM: conceptualization, funding acquisition, supervision, writing — review & editing. AS: conceptualization, methodology, investigation, supervision, writing — original draft, preparation, review & editing.

Corresponding authors

Correspondence to Christopher R. McCurdy or Abhisheak Sharma.

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Kamble, S.H., Berthold, E.C., Kanumuri, S.R.R. et al. Metabolism of Speciociliatine, an Overlooked Kratom Alkaloid for its Potential Pharmacological Effects. AAPS J 24, 86 (2022). https://doi.org/10.1208/s12248-022-00736-8

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