Cannabidiol, a Major Phytocannabinoid, As a Potent Atypical Inhibitor for CYP2D6

Yamaori, Satoshi; Okamoto, Yasuka; Yamamoto, Ikuo; Watanabe, Kazuhito

doi:10.1124/dmd.111.041384

Cited by 135 publications

(112 citation statements)

References 37 publications

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“…CBD is a potent inhibitor of CYP2D6 [60]. Following treatment with various antipsychotic agents, tardive dyskinesia appeared to be greater in patients with the poor metabolizer phenotype of CYP2D6, but the difference was not statistically significant [175].…”

Section: Cbd Enzyme Targets In Movement Disordersmentioning

confidence: 98%

“…It is unclear whether this is involved in the therapeutic effect of CBD in CNS disorders as evidence of CYP2C19 expression in brain remains conflicted [58,59]. Two other CYPs, CYP2C9 and CYP2D6, are also potential targets for CBD as CBD also completely inhibits their function at 10 μM [60,61]. However, CBD exerts a more potent effect upon CYP2C9 (IC 50 = 2.7 μM) than CYP2D6 (IC 50 = 6.01-6.52 μM).…”

Section: Enzymes Involved In Xenobiotic Metabolismmentioning

confidence: 99%

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Molecular Targets of Cannabidiol in Neurological Disorders

Bih

Chen

Nunn³

et al. 2015

Neurotherapeutics

462

323

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Cannabis has a long history of anecdotal medicinal use and limited licensed medicinal use. Until recently, alleged clinical effects from anecdotal reports and the use of licensed cannabinoid medicines are most likely mediated by tetrahydrocannabinol by virtue of: 1) this cannabinoid being present in the most significant quantities in these preparations; and b) the proportion:potency relationship between tetrahydrocannabinol and other plant cannabinoids derived from cannabis. However, there has recently been considerable interest in the therapeutic potential for the plant cannabinoid, cannabidiol (CBD), in neurological disorders but the current evidence suggests that CBD does not directly interact with the endocannabinoid system except in vitro at supraphysiological concentrations. Thus, as further evidence for CBD's beneficial effects in neurological disease emerges, there remains an urgent need to establish the molecular targets through which it exerts its therapeutic effects. Here, we conducted a systematic search of the extant literature for original articles describing the molecular pharmacology of CBD. We critically appraised the results for the validity of the molecular targets proposed. Thereafter, we considered whether the molecular targets of CBD identified hold therapeutic potential in relevant neurological diseases. The molecular targets identified include numerous classical ion channels, receptors, transporters, and enzymes. Some CBD effects at these targets in in vitro assays only manifest at high concentrations, which may be difficult to achieve in vivo, particularly given CBD's relatively poor bioavailability. Moreover, several targets were asserted through experimental designs that demonstrate only correlation with a given target rather than a causal proof. When the molecular targets of CBD that were physiologically plausible were considered for their potential for exploitation in neurological therapeutics, the results were variable. In some cases, the targets identified had little or no established link to the diseases considered. In others, molecular targets of CBD were entirely consistent with those already actively exploited in relevant, clinically used, neurological treatments. Finally, CBD was found to act upon a number of targets that are linked to neurological therapeutics but that its actions were not consistent withmodulation of such targets that would derive a therapeutically beneficial outcome. Overall, we find that while >65 discrete molecular targets have been reported in the literature for CBD, a relatively limited number represent plausible targets for the drug's action in neurological disorders when judged by the criteria we set. We conclude that CBD is very unlikely to exert effects in neurological diseases through modulation of the endocannabinoid system. Moreover, a number of other molecular targets of CBD reported in the literature are unlikely to be of relevance owing to effects only being observed at supraphysiological concentrations. Of interest and after excludin...

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Section: Cbd Enzyme Targets In Movement Disordersmentioning

confidence: 98%

Section: Enzymes Involved In Xenobiotic Metabolismmentioning

confidence: 99%

Molecular Targets of Cannabidiol in Neurological Disorders

Bih

Chen

Nunn³

et al. 2015

Neurotherapeutics

462

323

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“…Both Δ9-THC and CBD can inhibit CYP-450 metabolic activity, particularly the CYP2C isozymes at low concentrations and CYP3A4 isozymes at higher concentrations [284][285][286][287][288][289]. CYP2C and CYP3A4 are induced by carbamazepine, topiramate, and phenytoin, and inhibited valproate and other drugs [290].…”

Section: Safety Issuesmentioning

confidence: 99%

“…CYP2C and CYP3A4 are induced by carbamazepine, topiramate, and phenytoin, and inhibited valproate and other drugs [290]. The cannabinoids, particularly CBD, can inhibit other isozymes, including 2D6 and 1A1 [285,291]. Therefore, use of Δ9-THC or CBD could potentially contribute to bidirectional drug-drug interactions with antiepileptic and other drugs.…”

Section: Safety Issuesmentioning

confidence: 99%

Cannabinoids and Epilepsy

et al. 2015

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Cannabis has been used for centuries to treat seizures. Recent anecdotal reports, accumulating animal model data, and mechanistic insights have raised interest in cannabisbased antiepileptic therapies. In this study, we review current understanding of the endocannabinoid system, characterize the pro-and anticonvulsive effects of cannabinoids [e.g., Δ9-tetrahydrocannabinol and cannabidiol (CBD)], and highlight scientific evidence from pre-clinical and clinical trials of cannabinoids in epilepsy. These studies suggest that CBD avoids the psychoactive effects of the endocannabinoid system to provide a well-tolerated, promising therapeutic for the treatment of seizures, while whole-plant cannabis can both contribute to and reduce seizures. Finally, we discuss results from a new multicenter, open-label study using CBD in a population with treatment-resistant epilepsy. In all, we seek to evaluate our current understanding of cannabinoids in epilepsy and guide future basic science and clinical studies.

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“…CYP modulation is not just limited to tobacco use, as marijuana consumption is also implicated in altering CYP activity. For instance, cannabidiol, a component of marijuana, is a potent inhibitor of CYP2D6 [61]. Although CYP2D6 represents approximately 2% of total hepatic P450 content [62], it is responsible for the metabolism of a number of drug classes [63].…”

Section: Smoking Statusmentioning

confidence: 99%

Update and trends on pharmacokinetic studies in patients with impaired renal function: practical insight into application of the FDA and EMA guidelines

Paglialunga

Offman

Ichhpurani

et al. 2017

Expert Review of Clinical Pharmacology

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Introduction: The incidence of kidney dysfunction increases with age and is highly prevalent among patients with hypertension. Since many therapeutic compounds are primarily eliminated through the kidneys, impaired renal function can have negative consequences on drug disposition, efficacy and safety. Therefore, regulatory agencies such as the Food and Drug Administration (FDA) and European Medicines Agency (EMA) have issued detailed guidelines for new drug applications to determine posology requirements for patients with renal impairment. Areas covered: The current review highlights and contrasts agency requirements for pharmacokinetic renal impairment clinical studies. While many of the guidelines are similar among the two agencies, glomerular filtration rate (GFR) determination and reporting differ. Design considerations for a reduced, full or dialysis renal impairment study, as well as modifications to the FDA's draft guidance are discussed. Furthermore, scenarios where pharmacokinetic modelling analysis can benefit a drug development program are also reviewed. Moreover, practical solutions for patient recruitment challenges are addressed. Expert commentary: We summarize how 'one size does not fit all' for GFR assessment, and recommend when to use certain modalities. Finally, we highlight the need for the pharmaceutical industry to engage therapeutic experts to assist in protocol development for renal impairment studies, as these experts understand the nuances of this special population and recommended guidelines. ARTICLE HISTORY

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Cannabidiol, a Major Phytocannabinoid, As a Potent Atypical Inhibitor for CYP2D6

Cited by 135 publications

References 37 publications

Molecular Targets of Cannabidiol in Neurological Disorders

Molecular Targets of Cannabidiol in Neurological Disorders

Cannabinoids and Epilepsy

Update and trends on pharmacokinetic studies in patients with impaired renal function: practical insight into application of the FDA and EMA guidelines

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