Methods: We performed a structured search of bibliographic and drug databases for peer-reviewed literature using focused review questions.
Objective: This review consists of three parts, representing three different possibilities of interactions between cannabinoid receptor ligands of both exogenous and endogenous origin and cytochrome P450 enzymes (CYPs). The first part deals with cannabinoids as CYP substrates, the second summarizes current knowledge on the influence of various cannabinoids on the metabolic activity of CYP, and the third outline a possible involvement of the endocannabinoid system and cannabinoid ligands in the regulation of CYP liver activity.
Results: Biotransformation via a hydrolytic pathway is the major route of endocannabinoid metabolism and the deactivation of substrates is characteristic, in contrast to the minor oxidative pathway via CYP involved in the bioactivation reactions. Phytocannabinoids are extensively metabolized by CYPs. The enzymes CYP2C9, CYP2C19, and CYP3A4 catalyze most of their hydroxylations. Similarly, CYP represents a major metabolic pathway for both synthetic cannabinoids used therapeutically and drugs that are abused. In vitro experiments document the mostly CYP inhibitory activity of the major phytocannabinoids, with cannabidiol as the most potent inhibitor of many CYPs. The drug-drug interactions between cannabinoids and various drugs at the CYP level are reported, but their clinical relevance remains unclear. The direct activation/inhibition of nuclear receptors in the liver cells by cannabinoids may result in a change of CYP expression and activity. Finally, we hypothesize the interplay of central cannabinoid receptors with numerous nervous systems, resulting in a hormone-mediated signal towards nuclear receptors in hepatocytes.
Medicinal cannabis use has increased exponentially with widespread legalization around the world. Cannabis-based products are being used for numerous health conditions, often in conjunction with prescribed medications. The risk of clinically significant drug-drug interactions (DDIs) increases in this setting of polypharmacy, prompting concern among health care providers. Serious adverse events can result from DDIs, specifically those affecting CYP-mediated drug metabolism. Both cannabidiol (CBD) and Δ 9 -tetrahydrocannabinol (Δ 9 -THC), major constituents of cannabis, potently inhibit CYPs. Cannabis-based products contain an array of cannabinoids, many of which have limited data available regarding potential DDIs. This study assessed the inhibitory potential of 12 cannabinoids against CYP-mediated drug metabolism to predict the likelihood of clinically significant DDIs between cannabis-based therapies and conventional medications. Supersomes™ were used to screen the inhibitory potential of cannabinoids in vitro. Twelve cannabinoids were evaluated at the predominant drug-metabolizing isoforms: CYP3A4, CYP2D6, CYP2C9, CYP1A2, CYP2B6, and CYP2C19. The cannabinoids exhibited varied effects and potencies across the CYP isoforms. CYP2C9-mediated metabolism was inhibited by nearly all the cannabinoids with estimated Ki values of 0.2-3.2 μM. Most of the cannabinoids inhibited CYP2C19, whereas CYP2D6, CYP3A4, and CYP2B6 were either not affected or only partially inhibited by the cannabinoids. Effects of the cannabinoids on CYP2D6, CYP1A2, CYP2B6, and CYP3A4 metabolism were limited so in vivo DDIs mediated by these isoforms would not be predicted. CYP2C9-mediated metabolism was inhibited by cannabinoids at clinically relevant concentrations. In vivo DDI studies may be justified for CYP2C9 substrates with a narrow therapeutic index.
Keywords: CYP450; cannabidiol; cannabinoids; drug metabolism; drug-drug interactions.
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