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In vitro evaluation of mitragynine metabolism to 7-hydroxymitragynine and the influence of major cannabinoids

Philip Melchert
University of Florida

Co-Authors: Qingchen Zhang1, John S. Markowitz1
1University of Florida

Kratom (Mitragyna speciosa) is an indigenous tree native to Southeast Asia whose leaves have been traditionally ingested in a raw form by chewing or drinking as a tea. Kratom preparations are widely consumed in the US with an estimated usage prevalence of 1% and have been marketed in combination with cannabis products. Although kratom and its constituents presently have no FDA approved uses, it’s extracts or major alkaloids have psychoactive properties and may hold promise for the treatment of opioid cessation and pain management – in part due to its ability to partially agonize mu opioid receptors. Kratom’s pharmacological effects are attributed to its major alkaloids (e.g. mitragynine, 7-hydroxymitragynine). Although present in kratom extracts at low concentrations, 7-hydroxymitragynine is the primary metabolite formed by the metabolism of mitragynine and the most potent, thus it contributes to the overall pharmacodynamic effects of kratom extracts. Given its potential clinical applications, there is an interest in the potential for kratom extracts to interact with various drug metabolizing enzymes (DMEs) including those of the cytochrome P450 (CYP) family. CYP3A appears to be a major metabolic pathway for the conversion of mitragynine to 7-hydroxymitragine and the coadministration of cannabidiol (CBD) increased the systemic concentration of kratom alkaloids in a rodent model. However, the in vitro metabolism parameters of mitragynine metabolism mediated through the CYP3A isoform have yet to be well defined. In addition, the preliminary in vitro work investigating the impacts of known CYP3A inhibitors has not been thoroughly examined. Our hypothesis is that mitragynine’s conversion to 7-hydroxymitragynine through CYP3A mediated metabolism will be significantly impaired by known CYP3A inhibitors, such as the cannabinoids, CBD and -9-tetrahydrocannabinol (THC). Our ongoing studies utilizing human liver microsomes will establish the in vitro parameters of metabolism for mitragynine through CYP3A and its impact by CYP3A inhibitors. Both THC and CBD will be evaluated for its impact on the metabolism of mitragynine. This investigation will help elucidate the drug-drug interaction (DDI) potential of coadministering kratom extracts and cannabis-containing products.

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