Hepatic biotransformation of non-psychotropic phytocannabinoids and activity screening on cytochromes P450 and UDP-glucuronosyltransferases

Havlasek, Jakub; Vrba, Jiri; Zatloukalova, Martina; Papouskova, Barbora; Modriansky, Martin; Storch, Jan; Vacek, Jan

doi:10.1016/j.taap.2023.116654

Cited by 9 publications

(4 citation statements)

References 39 publications

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“…The first study to characterize the human hepatic biotransformation of CBC was conducted by Havlasek et al Of note, monoglucuronides represented nearly 50% of all CBC metabolites produced, followed by hydroxylation with 31% [ 53 ]. There are several critical caveats to their work.…”

Section: Discussionmentioning

confidence: 99%

Identification and Characterization of Cannabichromene’s Major Metabolite Following Incubation with Human Liver Microsomes

Ward,

Shokati,

Klawitter

et al. 2024

Metabolites

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Cannabichromene (CBC) is a minor cannabinoid within the array of over 120 cannabinoids identified in the Cannabis sativa plant. While CBC does not comprise a significant portion of whole plant material, it is available to the public in a purified and highly concentrated form. As minor cannabinoids become more popular due to their potential therapeutic properties, it becomes crucial to elucidate their metabolism in humans. Therefore, the goal of this was study to identify the major CBC phase I-oxidized metabolite generated in vitro following incubation with human liver microsomes. The novel metabolite structure was identified as 2′-hydroxycannabicitran using gas chromatography–mass spectrometry and nuclear magnetic resonance spectroscopy. Following the identification, in silico molecular modeling experiments were conducted and predicted 2′-hydroxycannabicitran to fit in the orthosteric site of both the CB1 and CB2 receptors. When tested in vitro utilizing a competitive binding assay, the metabolite did not show significant binding to either the CB1 or CB2 receptors. Further work necessitates the determination of potential activity of CBC and the here-identified phase I metabolite in other non-cannabinoid receptors.

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Section: Discussionmentioning

confidence: 99%

Identification and Characterization of Cannabichromene’s Major Metabolite Following Incubation with Human Liver Microsomes

Ward,

Shokati,

Klawitter

et al. 2024

Metabolites

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show abstract

“…The predominant metabolic clearance pathways for CBD are hydroxylation by the cytochrome P450 (P450) enzyme system at the methyl group located on the 7' position of the substituted cyclohexene ring, or less frequently at one of the carbons in the pentyl side chain (see Fig. 1) (Jiang et al, 2011;Beers et al, 2021), as well as direct glucuronidation by UDP-glucuronosyltransferase (UGT) enzymes (Havlasek et al, 2023). Of note, the major metabolite 7-hydroxy-CBD (7-OH-CBD) is pharmacologically active and contributes to the anticonvulsant effect of CBD (Whalley et al, 2017).…”

Section: Cbd Pharmacokinetics In Humansmentioning

confidence: 99%

“…While prior in vitro studies using human liver microsomes and recombinant P450s cite CYP3A4 as the major enzyme involved in 7-COOH-CBD formation (Epidiolex ® , 2018), recent studies with human liver cytosol and S9 fraction have shown that 7-COOH-CBD formation is largely NAD + -dependent, with smaller contributions from NADPH-dependent enzymes (i.e., P450 enzymes) (Beers et al, 2023). In addition to P450 metabolism, CBD is glucuronidated by UGT1A3, UGT1A7, UGT1A8, UGT1A9, and UGT2B7 to form CBD-O-glucuronide as well as other minor glucuronidated metabolites (Mazur et al, 2009;Havlasek et al, 2023). Of note, both CBD and its metabolite 7-OH-CBD are known to participate in multiple pharmacokinetic drug-drug interactions (DDIs) mediated by CYPs and UGTs.…”

Section: Cbd Pharmacokinetics In Humansmentioning

confidence: 99%

Advances and Challenges in Modeling Cannabidiol Pharmacokinetics and Hepatotoxicity

Beers,

Zhou,

Jackson

2024

Drug Metab Dispos

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LC-MS/MS, Liquid chromatography-tandem mass spectrometry; MRP1, Multidrug resistance-associated protein 1; MRP2, Multidrug resistance-associated protein 2; NRF2 or NFELE2, Nuclear factor erythroid 2-related factor 2; NTCP, Sodium taurocholate co-transporting polypeptide; OATP, organic anion transporting polypeptide; OCT, Ornithine carbamyltransferase; OSTα/β, organic solute transporter α and β; P450 or CYP, Cytochrome P450; PBPK, Physiologically based pharmacokinetic (model); Pgp, P-glycoprotein; PPAR-α or PPARA, Peroxisome proliferator activated receptor alpha; QST, quantitative systems toxicology; ROS, reactive oxygen species; THC, Delta-9-tetrahydrocannabinol; TPRA1, Transient receptor potential ankyrin type 1; TRPM8, Transient receptor potential of melastatin type 8 channel; TRPV1, Transient receptor potential vanilloid-type 1; UDPGA, Uridine 5'-diphosphate glucuronic acid; UGT, Uridine 5'-diphospho-glucuronosyltransferase; ULN, Upper limit of normal; VDAC1, Voltage-dependent anion channel 1; VPA, Valproic acid or valproate.

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“…From further studies, it is known that CBD also contributes to the inhibition of UDPglururonosyltransferases. 13 With respect to ABC efflux transporters, it appears to inhibit ABCC1, but not the major drug transporters ABCB1 (P-gp) and ABCG2 (BCRP). CBD and THX are also mentioned as inhibitors of the nucleoside transporter ENT1 and ENT2.…”

mentioning

confidence: 99%

Clinical Pharmacology of Cannabinoid Therapeutics: Drug Interactions and Side Effects

Cascorbi

2023

Clin Pharma and Therapeutics

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Hepatic biotransformation of non-psychotropic phytocannabinoids and activity screening on cytochromes P450 and UDP-glucuronosyltransferases

Cited by 9 publications

References 39 publications

Identification and Characterization of Cannabichromene’s Major Metabolite Following Incubation with Human Liver Microsomes

Identification and Characterization of Cannabichromene’s Major Metabolite Following Incubation with Human Liver Microsomes

Advances and Challenges in Modeling Cannabidiol Pharmacokinetics and Hepatotoxicity

Clinical Pharmacology of Cannabinoid Therapeutics: Drug Interactions and Side Effects

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