Refined Prediction of Pharmacokinetic Kratom-Drug Interactions: Time-Dependent Inhibition Considerations

Tanna, Rakshit S.; Tian, Dandan; Cech, Nadja B.; Oberlies, Nicholas H.; Rettie, Allan E.; Thummel, Kenneth E.; Paine, Mary F.

doi:10.1124/jpet.120.000270

Cited by 25 publications

(45 citation statements)

References 66 publications

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“…Kratom has been associated with biliary cholangitis and cholestasis in several cases (67,(103)(104)(105)(106)(107)(108)(109)(110) and with one case of hepatomegaly (111), but also with acute hepatitis (112). Mitragynine inhibits hepatic and intestinal cytochrome P450 3A activities (113) and hepatic microsomal CYP2D6 (114), thus increasing blood levels of other concomitantly administered drugs that are metabolized by these isoenzymes, that is, most psychiatric drugs. This may expose to further hepatotoxicity (115,116).…”

Section: Discussionmentioning

confidence: 99%

Case Report: Treatment of Kratom Use Disorder With a Classical Tricyclic Antidepressant

Vento

Persis²,

Filippis³

et al. 2021

Front. Psychiatry

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Kratom or Mitragyna speciosa (Korth.) is an evergreen tree of the coffee family native to South-East Asia and Australasia. It is used by locals recreationally to induce stimulant and sedative effects and medically to soothe pain and opiate withdrawal. Its leaves are smoked, chewed, or infused, or ground to yield powders or extracts for use as liquids. It contains more than 40 alkaloids; among these, mitragynine and 7-hydroxymitragynine are endowed with variable mu, delta, and kappa opioid stimulating properties (with 7-hydroxymitragynine having a more balanced affinity), rhynchophylline, which is a non-competitive NMDA glutamate receptor antagonist, but is present in negligible quantities, and raubasine, which inhibits α1-adrenceptors preferentially over α2-adrenceptors, while the latter are bound by 7-hydroxymitragynine, while mitragynine counters 5-HT2A receptors. This complexity of neurochemical mechanisms may account for kratom's sedative-analgesic and stimulant effects. It is commonly held that kratom at low doses is stimulant and at higher doses sedative, but no cut-off has been possible to define. Long-term use of kratom may produce physical and psychological effects that are very similar to its withdrawal syndrome, that is, anxiety, irritability, mood, eating, and sleep disorders, other than physical symptoms resembling opiate withdrawal. Kratom's regulatory status varies across countries; in Italy, both mitragynine and the entire tree and its parts are included among regulated substances. We describe the case of a patient who developed anxiety and dysphoric mood and insomnia while using kratom, with these symptoms persisting after withdrawal. He did not respond to a variety of antidepressant combinations and tramadol for various months, and responded after 1 month of clomipramine. Well-being persisted after discontinuing tramadol.

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Section: Discussionmentioning

confidence: 99%

Case Report: Treatment of Kratom Use Disorder With a Classical Tricyclic Antidepressant

Vento

Persis²,

Filippis³

et al. 2021

Front. Psychiatry

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“…Mitragynine was initially thought not to effectively inhibit the CYP3A4 isoform in a bioluminescent experiment with an IC 50 of 41.32 µM (Hanapi et al, 2013). Subsequent studies with HLM support the previous data but with a much lower IC 50 of < 20 µM when FDA recommended CYP3A4 probe substrate midazolam was used (Kamble et al, 2020;Tanna et al, 2021). Mitragynine also appears to inhibit CYP3A4 catalyzed midazolam hydroxylation in human intestinal microsomes (HIM) with IC 50 21.9 µM (Tanna et al, 2021).…”

Section: Potential Drug-drug Interactionsmentioning

confidence: 94%

“…It is obvious from the preceding section that mitragynine and other related alkaloids are substrates for multiple CYP isoforms and hence may interfere with metabolisms of clinical drugs. Preclinical research on mitragynine and related alkaloids on DDI is limited but has been gaining attention within the last 10 years ( Hanapi et al, 2013 ; Lim et al, 2013 ; Kamble et al, 2020 ; Todd et al, 2020 ; Tanna et al, 2021 ). Here, the focus is on the effect of mitragynine and related alkaloids on DMEs from in vitro preclinical research, and their utility to predict clinical DDI.…”

Section: Interactions With Enzymesmentioning

confidence: 99%

“…An AUCR > 1.25 may suggest potential clinical DDI ( Food and Drug Administration Center for Drug Evaluation and Research, 2020 ). The cut-off point of K i < 12 µM to group mitragynine and other alkaloids as a potential clinical inhibitor of DMEs in this review was based on the guidelines provided by Tanna et al (2021) . Mitragynine K i value from DMEs inhibition study <12 µM denote potential clinical relevance of CYP inhibition, determined relative to the highest mitragynine concentration quantified from autopsy blood samples of kratom-related death ( Gershman et al, 2019 ; Tanna et al, 2021 ).…”

Section: Interactions With Enzymesmentioning

confidence: 99%

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Kratom Alkaloids: Interactions With Enzymes, Receptors, and Cellular Barriers

et al. 2021

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Parallel to the growing use of kratom, there is a wealth of evidence from self-report, preclinical, and early clinical studies on therapeutic benefits of its alkaloids in particular for treating pain, managing substance use disorder, and coping with emotional or mental health conditions. On the other hand, there are also reports on potential health risks concerning kratom use. These two aspects are often discussed in reviews on kratom. Here, we aim to highlight specific areas that are of importance to give insights into the mechanistic of kratom alkaloids pharmacological actions. This includes their interactions with drug-metabolizing enzymes and predictions of clinical drug-drug interactions, receptor-binding properties, interactions with cellular barriers in regards to barrier permeability, involvement of membrane transporters, and alteration of barrier function when exposed to the alkaloids.

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“…It is well known that ketoconazole and rifampicin are often recommended to assess potential DDIs for other drugs mainly metabolized by the CYP3A4 enzyme ( Rytkönen et al, 2020 ; Xu et al, 2021 ). To our knowledge, owing to irreversible loss of P450 enzyme functions, TDIs are regarded to have a longer persistent time on the drug metabolic enzyme and consequently to cause clinically more significant DDIs in contrast to competitive inhibitors ( Kosaka et al, 2017 ; Eng et al, 2020 ; Tanna et al, 2021 ). Therefore, ketoconazole, delavirdine, and rifampicin were chosen for potential DDI assessments.…”

Section: Introductionmentioning

confidence: 99%

Effect of CYP3A4 Inhibitors and Inducers on Pharmacokinetics and Pharmacodynamics of Saxagliptin and Active Metabolite M2 in Humans Using Physiological-Based Pharmacokinetic Combined DPP-4 Occupancy

Li¹,

Liu

et al. 2021

Front. Pharmacol.

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We aimed to develop a physiological-based pharmacokinetic and dipepidyl peptidase 4 (DPP-4) occupancy model (PBPK-DO) characterized by two simultaneous simulations to predict pharmacokinetic (PK) and pharmacodynamic changes of saxagliptin and metabolite M2 in humans when coadministered with CYP3A4 inhibitors or inducers. Ketoconazole, delavirdine, and rifampicin were selected as a CYP3A4 competitive inhibitor, a time-dependent inhibitor, and an inducer, respectively. Here, we have successfully simulated PK profiles and DPP-4 occupancy profiles of saxagliptin in humans using the PBPK-DO model. Additionally, under the circumstance of actually measured values, predicted results were good and in line with observations, and all fold errors were below 2. The prediction results demonstrated that the oral dose of saxagliptin should be reduced to 2.5 mg when coadministrated with ketoconazole. The predictions also showed that although PK profiles of saxagliptin showed significant changes with delavirdine (AUC 1.5-fold increase) or rifampicin (AUC: a decrease to 0.19-fold) compared to those without inhibitors or inducers, occupancies of DPP-4 by saxagliptin were nearly unchanged, that is, the administration dose of saxagliptin need not adjust when there is coadministration with delavirdine or rifampicin.

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Refined Prediction of Pharmacokinetic Kratom-Drug Interactions: Time-Dependent Inhibition Considerations

Cited by 25 publications

References 66 publications

Case Report: Treatment of Kratom Use Disorder With a Classical Tricyclic Antidepressant

Case Report: Treatment of Kratom Use Disorder With a Classical Tricyclic Antidepressant

Kratom Alkaloids: Interactions With Enzymes, Receptors, and Cellular Barriers

Effect of CYP3A4 Inhibitors and Inducers on Pharmacokinetics and Pharmacodynamics of Saxagliptin and Active Metabolite M2 in Humans Using Physiological-Based Pharmacokinetic Combined DPP-4 Occupancy

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