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Background and Objectives <p>Kratom, a Southeast Asian tree, has been researched for its potential as a therapeutic for substance use disorders. The most abundant alkaloid in kratom, mitragynine, is being investigated individually for opioid use disorder. However, the active metabolite of mitragynine,7-hydroxymitragynine (7-HMG) has raised concerns because of its high binding affinity to μ-opioid receptors and abuse potential. This study examines various pharmacokinetic parameters of 7-HMG in both in vitro and in vivo models.</p> Methods <p>In vitro pharmacokinetic properties were investigated using human colorectal adenocarcinoma cell monolayers (Caco-2 cells), rat plasma, rat liver microsomes, and rat hepatocytes to determine the permeability, plasma protein binding, and microsomal and hepatocyte stability of 7-HMG, respectively. Oral and intravenous (IV) pharmacokinetic studies of 7-HMG were performed in male Sprague-Dawley rats.</p> Results <p>7-HMG exhibits high permeability across Caco-2 cells (19.7 ± 1.0 × 10<sup>−6</sup>&#xa0;cm/s), with a relatively low plasma protein binding of 73.1 ± 0.6% to mitragynine. The hepatic extraction ratio was 0.3 and 0.6 in rat liver microsomes and hepatocytes, respectively, indicating that 7-HMG is an intermediate hepatic extraction compound. Oral and IV pharmacokinetic studies were performed in male rats. The volume of distribution was 2.7 ± 0.4&#xa0;l/kg and the clearance was 4.0 ± 0.3&#xa0;l/h/kg after IV administration. After oral dosing&#xa0;(5 mg/kg), a <i>C</i><sub>max</sub> of 28.5 ± 5.0 ng/ml and <i>T</i><sub>max</sub> of 0.3 ± 0.1 h were observed. However, the oral bioavailability of 7-HMG was only 2.7 ± 0.3%. The results demonstrate 7-HMG is rapidly absorbed but has low oral bioavailability. Mitragynine pseudoindoxyl (MGPI) is a metabolite of 7-HMG that is a more potent µ-opioid agonist than 7-HMG. The parent-to-metabolite ratio for MGPI following IV 7-HMG administration was 0.5 ± 0.1%, indicating very limited systemic exposure to MGPI.</p> Conclusions <p>This study reports the pharmacokinetic parameters of 7-HMG to help with the development of mitragynine, as a therapeutic.</p>

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In Vitro and In Vivo Pharmacokinetic Characterization of 7-Hydroxymitragynine, an Active Metabolite of Mitragynine, in Sprague-Dawley Rats

  • 期刊论文

  • 发表日期：

    2025年3月22日

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  • Yi-Hua Chiang,
  • Siva Rama Raju Kanumuri,
  • Michelle A. Kuntz,
  • Alexandria S. Senetra,
  • Erin C. Berthold,
  • Shyam H. Kamble,
  • Sushobhan Mukhopadhyay,
  • Aidan J. Hampson,
  • Christopher R. McCurdy,
  • Abhisheak Sharma

摘要

Background and Objectives

Kratom, a Southeast Asian tree, has been researched for its potential as a therapeutic for substance use disorders. The most abundant alkaloid in kratom, mitragynine, is being investigated individually for opioid use disorder. However, the active metabolite of mitragynine,7-hydroxymitragynine (7-HMG) has raised concerns because of its high binding affinity to μ-opioid receptors and abuse potential. This study examines various pharmacokinetic parameters of 7-HMG in both in vitro and in vivo models.

Methods

In vitro pharmacokinetic properties were investigated using human colorectal adenocarcinoma cell monolayers (Caco-2 cells), rat plasma, rat liver microsomes, and rat hepatocytes to determine the permeability, plasma protein binding, and microsomal and hepatocyte stability of 7-HMG, respectively. Oral and intravenous (IV) pharmacokinetic studies of 7-HMG were performed in male Sprague-Dawley rats.

Results

7-HMG exhibits high permeability across Caco-2 cells (19.7 ± 1.0 × 10−6 cm/s), with a relatively low plasma protein binding of 73.1 ± 0.6% to mitragynine. The hepatic extraction ratio was 0.3 and 0.6 in rat liver microsomes and hepatocytes, respectively, indicating that 7-HMG is an intermediate hepatic extraction compound. Oral and IV pharmacokinetic studies were performed in male rats. The volume of distribution was 2.7 ± 0.4 l/kg and the clearance was 4.0 ± 0.3 l/h/kg after IV administration. After oral dosing (5 mg/kg), a Cmax of 28.5 ± 5.0 ng/ml and Tmax of 0.3 ± 0.1 h were observed. However, the oral bioavailability of 7-HMG was only 2.7 ± 0.3%. The results demonstrate 7-HMG is rapidly absorbed but has low oral bioavailability. Mitragynine pseudoindoxyl (MGPI) is a metabolite of 7-HMG that is a more potent µ-opioid agonist than 7-HMG. The parent-to-metabolite ratio for MGPI following IV 7-HMG administration was 0.5 ± 0.1%, indicating very limited systemic exposure to MGPI.

Conclusions

This study reports the pharmacokinetic parameters of 7-HMG to help with the development of mitragynine, as a therapeutic.