The Lack of Contribution of 7-Hydroxymitragynine to the Antinociceptive Effects of Mitragynine in Mice: A Pharmacokinetic and Pharmacodynamic Study

Berthold, Erin C.; Kamble, Shyam H.; Raju, K. Kanaka; Kuntz, Michelle A.; Senetra, Alexandria S.; Mottinelli, Marco; León, Francisco; Restrepo, Luís Fernando; Patel, Avi; Ho, Nicholas P.; Hiranita, Takato; Sharma, Abhisheak; McCurdy, Christopher R.

doi:10.1124/dmd.121.000640

Cited by 18 publications

(15 citation statements)

References 41 publications

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“…The observed antinociceptive effects decreased when the μ -opioid receptor antagonist naltrexone was administered intraperitoneally, suggesting that these effects are primarily μ -opioid receptor mediated. Although 7-hydroxymitragynine is more potent than mitragynine, its role in the overall antinociceptive effect after mitragynine administration is inconclusive, largely due to the lower brain concentration of 7-hydroxymitragynine ( Berthold et al, 2022 ). Mitragynine was shown to have more potent effects in rodent models when administered orally compared with intraperitoneal or subcutaneous routes, suggesting potential first-pass bioactivation of this alkaloid to more potent metabolites ( Kruegel and Grundmann, 2018 ).…”

Section: Pharmacologymentioning

confidence: 99%

Translating Kratom-Drug Interactions: From Bedside to Bench and Back

Tanna

Cech²,

Oberlies

et al. 2023

Drug Metab Dispos

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Kratom is a botanical natural product belonging to the coffee family, with stimulant effects at low doses and opioid-like effects at higher doses. During the last two decades, kratom has been purported as a safer alternative to pharmaceutical and illicit drugs to self-manage pain and opioid withdrawal symptoms. Kratom alkaloids, typically mitragynine, have been detected in biologic samples from overdose deaths. These deaths are often observed in combination with other drugs and are suspected to result from polyintoxications. This review focuses on the potential for kratom to precipitate pharmacokinetic interactions with object drugs involved in these reported polyintoxications. The legal status, chemistry, pharmacology, and toxicology are also summarized. The aggregate in vitro and clinical data identified kratom and select kratom alkaloids as modulators of cytochrome P450 (P450) enzyme activity, notably as inhibitors of CYP2D6 and CYP3A, as well as P-glycoprotein–mediated efflux activity. These inhibitory effects could increase the systemic exposure to co-consumed object drugs, which may lead to adverse effects. Collectively, the evidence to date warrants further evaluation of potential kratom-drug interactions using an iterative approach involving additional mechanistic in vitro studies, well designed clinical studies, and physiologically based pharmacokinetic modeling and simulation. This critical information is needed to fill knowledge gaps regarding the safe and effective use of kratom, thereby addressing ongoing public health concerns. SIGNIFICANCE STATEMENT The botanical kratom is increasingly used to self-manage pain and opioid withdrawal symptoms due to having opioid-like effects. The legal status, chemistry, pharmacology, toxicology, and drug interaction potential of kratom are reviewed. Kratom-associated polyintoxications and in vitro-in vivo extrapolations suggest that kratom can precipitate pharmacokinetic drug interactions by inhibiting CYP2D6, CYP3A, and P-glycoprotein. An iterative approach that includes clinical studies and physiologically based pharmacokinetic modeling and simulation is recommended for further evaluation of potential unwanted kratom-drug interactions.

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Section: Pharmacologymentioning

confidence: 99%

Translating Kratom-Drug Interactions: From Bedside to Bench and Back

Tanna

Cech²,

Oberlies

et al. 2023

Drug Metab Dispos

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“…However, other studies showed that 7-OH MG does contribute to the analgesic and respiratory depressive effects of MG, albeit its contribution was found to be limited by metabolic saturation (Kruegel et al, 2019;Chakraborty et al, 2021;Hill et al, 2022). In the study by Berthold and colleagues it was demonstrated that in mice treated with MG doses which produced significant hotplate antinociception, 7-OH-MG brain levels remained significantly below the observed 7-OH-MG brain levels found in 7-OH-MG treated mice that were dosed sufficiently to produce acute antinociception (Berthold et al, 2022). In this study, the pharmacological activity of 7-OH-MG was quite different from that of MG, which contradicts the hypothesis that 7-OH-MG is responsible for the "apparent" antinociceptive effects of MG in mice (Kruegel et al, 2019).…”

Section: Discussionmentioning

confidence: 98%

“…It is worth noting that MG is metabolized by CYP3A4 to 7-OH-MG (Kamble et al, 2019;Basiliere and Kerrigan, 2020;Chakraborty et al, 2021). It was recently reported that metabolic conversion of 7-OH-MG does not contribute to MG pharmacological activity (Berthold et al, 2022). However, other studies showed that 7-OH MG does contribute to the analgesic and respiratory depressive effects of MG, albeit its contribution was found to be limited by metabolic saturation (Kruegel et al, 2019;Chakraborty et al, 2021;Hill et al, 2022).…”

Section: Discussionmentioning

confidence: 99%

Interactive Effects ofµ-Opioid and Adrenergic-α₂Receptor Agonists in Rats: Pharmacological Investigation of the Primary Kratom Alkaloid Mitragynine and Its Metabolite 7-Hydroxymitragynine

Obeng

León

Patel

et al. 2022

J Pharmacol Exp Ther

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Non-standard abbreviations: δ-opioid receptor (DOR), κ-opioid receptor (KOR), µ-opioid receptor (MOR), 69,593), 2-(2,3-dihydro-2-methoxy-1,4-benzodioxin-2-yl)-4,5-dihydro-1H-imidazole (RX821002), 7hydroxymitagynine (7-OH-MG), Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC), analysis of variance (ANOVA), adrenergic-α 2 (Aα 2 R), Chinese hamster ovary (CHO), [D-Ala 2 , D-Leu 5 ]-Enkephalin (DADLE), [D-Ala 2 , N-MePhe 4 , Gly-ol]-enkephalin (DAMGO), ethylene glycolbis(β-aminoethyl ether)-N,N,N′,N′-tetraacetic acid (EGTA), fixed ratio (FR), human embryonic kidney (HEK), inhibition constant (Ki), Institutional Animal Care and Use Committee (IACUC), intraperitoneally (i.p.), intrathecally (i.t.), light-emitting diode (LED), mitragynine (MG), National Institutes of Health (NIH), orally by gavage (p.o.), percent maximum possible antinociceptive effect (% MPE), standard error of mean (SEM), subcutaneously (s.c.), Tris, MgCl 2 , and ethylene glycol-bis(β-aminoethyl ether)-N,N,N′,N′-tetraacetic acid (TME)

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“…The higher potency and MOR efficacy of 7HMG compared to mitragynine is often assumed to indicate that 7HMG is a driver of kratom's MOR activity (Kruegel et al, 2019). However, a recent study in mice reported that 7HMG administered at a dose sufficient to achieve plasma concentrations similar to those resulting from an oral mitragynine dose, does not induce similar levels of antinociception (Berthold et al, 2022). This result suggests that 7HMG formation does not contribute to the effects of mitragynine.…”

mentioning

confidence: 99%

“…7HMG is also found as a circulating metabolite after mitragynine administration in mice, rats, dogs, and humans (Hiranita et al, 2020;Maxwell et al, 2020;Berthold et al, 2022;Tanna et al, 2022). Mitragynine binds to a number of receptors including the μ-opioid receptor (MOR), to which 7HMG also binds (Obeng et al, 2019).…”

mentioning

confidence: 99%

Pharmacokinetic and Pharmacodynamic Consequences of Cytochrome P450 3A Inhibition on Mitragynine Metabolism in Rats

Kamble

Obeng

León

et al. 2023

J Pharmacol Exp Ther

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Non-standard abbreviations: Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC), analysis of variance (ANOVA), area under the plasma concentrationtime curve (AUC ), carboxymethyl cellulose sodium salt (Na-CMC), Chinese hamster ovary (CHO), confidence interval (CI), cytochrome P450 3A (CYP3A), [D-Ala 2 , D-Leu 5 ]-Enkephalin (DADLE), [D-Ala 2 , N-MePhe 4 , Gly-ol]-enkephalin (DAMGO), δ-opioid receptor (DOR), fixed ratio (FR), guanosine 5'-O-[g-thio]triphosphate (GTPgS), human embryonic kidney (HEK), Institutional Animal Care and Use Committee (IACUC), intraperitoneally (i.p.), internal standard (IS), k-opioid receptor (KOR), light-emitting diode (LED), µ-opioid receptor (MOR), maximum possible effect (MPE), oral gavage (o.g.), nicotinamide adenine dinucleotide phosphate reduced tetrasodium salt (NADPH), National

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The Lack of Contribution of 7-Hydroxymitragynine to the Antinociceptive Effects of Mitragynine in Mice: A Pharmacokinetic and Pharmacodynamic Study

Cited by 18 publications

References 41 publications

Translating Kratom-Drug Interactions: From Bedside to Bench and Back

Translating Kratom-Drug Interactions: From Bedside to Bench and Back

Interactive Effects ofµ-Opioid and Adrenergic-α₂Receptor Agonists in Rats: Pharmacological Investigation of the Primary Kratom Alkaloid Mitragynine and Its Metabolite 7-Hydroxymitragynine

Pharmacokinetic and Pharmacodynamic Consequences of Cytochrome P450 3A Inhibition on Mitragynine Metabolism in Rats

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The Lack of Contribution of 7-Hydroxymitragynine to the Antinociceptive Effects of Mitragynine in Mice: A Pharmacokinetic and Pharmacodynamic Study

Cited by 18 publications

References 41 publications

Translating Kratom-Drug Interactions: From Bedside to Bench and Back

Translating Kratom-Drug Interactions: From Bedside to Bench and Back

Interactive Effects ofµ-Opioid and Adrenergic-α2Receptor Agonists in Rats: Pharmacological Investigation of the Primary Kratom Alkaloid Mitragynine and Its Metabolite 7-Hydroxymitragynine

Pharmacokinetic and Pharmacodynamic Consequences of Cytochrome P450 3A Inhibition on Mitragynine Metabolism in Rats

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Interactive Effects ofµ-Opioid and Adrenergic-α₂Receptor Agonists in Rats: Pharmacological Investigation of the Primary Kratom Alkaloid Mitragynine and Its Metabolite 7-Hydroxymitragynine