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

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 ± 0.7min, respectively), while a slower metabolism was observed in human and dog hepatocytes (91.7 ± 12.8 and > 120min, 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.