An in vitro evaluation of kratom (Mitragyna speciosa) on the catalytic activity of carboxylesterase 1 (CES1)

Philip W Melchert; Qingchen Zhang; Sushobhan Mukhopadhyay; Siva Rama Raju Kanumuri; Christopher R McCurdy; John S Markowitz

doi:10.1016/j.cbi.2023.110715

An in vitro evaluation of kratom (Mitragyna speciosa) on the catalytic activity of carboxylesterase 1 (CES1)

Chem Biol Interact. 2023 Oct 1:384:110715. doi: 10.1016/j.cbi.2023.110715. Epub 2023 Sep 15.

Authors

Philip W Melchert¹, Qingchen Zhang², Sushobhan Mukhopadhyay³, Siva Rama Raju Kanumuri⁴, Christopher R McCurdy³, John S Markowitz²

Affiliations

¹ Department of Pharmacotherapy and Translational Research, University of Florida, Gainesville, FL, USA. Electronic address: melchertphilip@ufl.edu.
² Department of Pharmacotherapy and Translational Research, University of Florida, Gainesville, FL, USA.
³ Department of Medicinal Chemistry, University of Florida, Gainesville, FL, USA.
⁴ Department of Pharmaceutics, University of Florida, Gainesville, FL, USA.

PMID: 37716419
PMCID: PMC10606955 (available on 2024-10-01)
DOI: 10.1016/j.cbi.2023.110715

Abstract

Kratom, (Mitragyna Speciosa Korth.) is a plant indigenous to Southeast Asia whose leaves are cultivated for a variety of medicinal purposes and mostly consumed as powders or tea in the United States. Kratom use has surged in popularity with the lay public and is currently being investigated for possible therapeutic benefits including as a treatment for opioid withdrawal due to the pharmacologic effects of its indole alkaloids. A wide array of psychoactive compounds are found in kratom, with mitragynine being the most abundant alkaloid. The drug-drug interaction (DDI) potential of mitragynine and related alkaloids have been evaluated for effects on the major cytochrome P450s (CYPs) via in vitro assays and limited clinical investigations. However, no thorough assessment of their potential to inhibit the major hepatic hydrolase, carboxylesterase 1 (CES1), exists. The purpose of this study was to evaluate the in vitro inhibitory potential of kratom extracts and its individual major alkaloids using an established CES1 assay and incubation system. Three separate kratom extracts and the major kratom alkaloids mitragynine, speciogynine, speciociliatine, paynantheine, and corynantheidine displayed a concentration-dependent reversible inhibition of CES1. The experimental K_i values were determined as follows for mitragynine, speciociliatine, paynantheine, and corynantheidine: 20.6, 8.6, 26.1, and 12.5 μM respectively. Speciociliatine, paynantheine, and corynantheidine were all determined to be mixed-type reversible inhibitors of CES1, while mitragynine was a purely competitive inhibitor. Based on available pharmacokinetic data, determined Ki values, and a physiologically based inhibition screen mimicking alkaloid exposures in humans, a DDI mediated via CES1 inhibition appears unlikely across a spectrum of doses (i.e., 2-20g per dose). However, further clinical studies need to be conducted to exclude the possibility of a DDI at higher and extreme doses of kratom and those who are chronic users.

Keywords: CES1; Kratom alkaloids; Mitragyna speciosa; Mitragynine.

MeSH terms

Carboxylic Ester Hydrolases
Humans
Mitragyna*
Plant Extracts / pharmacology

Substances

Plant Extracts
Carboxylic Ester Hydrolases
CES1 protein, human

Abstract

MeSH terms

Substances

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