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
{"title":"米特拉金的活性代谢物7-羟基米特拉金在Sprague-Dawley大鼠体内外药动学表征","authors":"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","doi":"10.1007/s13318-025-00939-2","DOIUrl":null,"url":null,"abstract":"<p><strong>Background and objectives: </strong>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><p><strong>Methods: </strong>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><p><strong>Results: </strong>7-HMG exhibits high permeability across Caco-2 cells (19.7 ± 1.0 × 10<sup>-6</sup> 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 C<sub>max</sub> of 28.5 ± 5.0 ng/ml and T<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><p><strong>Conclusions: </strong>This study reports the pharmacokinetic parameters of 7-HMG to help with the development of mitragynine, as a therapeutic.</p>","PeriodicalId":11939,"journal":{"name":"European Journal of Drug Metabolism and Pharmacokinetics","volume":" ","pages":""},"PeriodicalIF":1.9000,"publicationDate":"2025-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"In Vitro and In Vivo Pharmacokinetic Characterization of 7-Hydroxymitragynine, an Active Metabolite of Mitragynine, in Sprague-Dawley Rats.\",\"authors\":\"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\",\"doi\":\"10.1007/s13318-025-00939-2\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background and objectives: </strong>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><p><strong>Methods: </strong>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><p><strong>Results: </strong>7-HMG exhibits high permeability across Caco-2 cells (19.7 ± 1.0 × 10<sup>-6</sup> 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 C<sub>max</sub> of 28.5 ± 5.0 ng/ml and T<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><p><strong>Conclusions: </strong>This study reports the pharmacokinetic parameters of 7-HMG to help with the development of mitragynine, as a therapeutic.</p>\",\"PeriodicalId\":11939,\"journal\":{\"name\":\"European Journal of Drug Metabolism and Pharmacokinetics\",\"volume\":\" \",\"pages\":\"\"},\"PeriodicalIF\":1.9000,\"publicationDate\":\"2025-03-22\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"European Journal of Drug Metabolism and Pharmacokinetics\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1007/s13318-025-00939-2\",\"RegionNum\":4,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q3\",\"JCRName\":\"PHARMACOLOGY & PHARMACY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"European Journal of Drug Metabolism and Pharmacokinetics","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1007/s13318-025-00939-2","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}
In Vitro and In Vivo Pharmacokinetic Characterization of 7-Hydroxymitragynine, an Active Metabolite of Mitragynine, in Sprague-Dawley Rats.
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.
期刊介绍：
Hepatology International is a peer-reviewed journal featuring articles written by clinicians, clinical researchers and basic scientists is dedicated to research and patient care issues in hepatology. This journal focuses mainly on new and emerging diagnostic and treatment options, protocols and molecular and cellular basis of disease pathogenesis, new technologies, in liver and biliary sciences.
Hepatology International publishes original research articles related to clinical care and basic research; review articles; consensus guidelines for diagnosis and treatment; invited editorials, and controversies in contemporary issues. The journal does not publish case reports.
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