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Cannabidiol is a potent inhibitor of the catalytic activity of cytochrome P450 2C19.
Drug Metab Pharmacokinet. 2013; 28(4):332-8.DM

Abstract

The present study investigated the inhibitory effect of cannabidiol (CBD), a major constituent of marijuana, on the catalytic activity of cytochrome P450 2C19 (CYP2C19). (S)-Mephenytoin 4'-hydroxylase activities of human liver microsomes (HLMs) and recombinant CYP2C19 were inhibited by CBD in a concentration-dependent manner (IC₅₀ = 8.70 and 2.51 µM, respectively). Omeprazole 5-hydroxylase and 3-O-methylfluorescein O-demethylase activities in recombinant CYP2C19 were also strongly inhibited by CBD (IC₅₀ = 1.55 and 1.79 µM, respectively). Kinetic analysis for inhibition revealed that CBD showed a mixed-type inhibition against (S)-mephenytoin 4'-hydroxylation by recombinant CYP2C19. To clarify the structural requirements for CBD-mediated CYP2C19 inhibition, the effects of CBD-related compounds on CYP2C19 activity were examined. Olivetol inhibited the (S)-mephenytoin 4'-hydroxylase activity of recombinant CYP2C19 with the IC₅₀ value of 15.3 µM, whereas d-limonene slightly inhibited the activity (IC₅₀ > 50 µM). The inhibitory effect of CBD-2'-monomethyl ether (IC₅₀ = 1.88 µM) on CYP2C19 was comparable to that of CBD, although the inhibitory potency of CBD-2',6'-dimethyl ether (IC₅₀ = 14.8 µM) was lower than that of CBD. Cannabidivarin, possessing a propyl side chain, showed slightly less potent inhibition (IC₅₀ = 3.45 µM) as compared with CBD, whereas orcinol and resorcinol did not inhibit CYP2C19 activity at all. These results indicate that CBD caused potent CYP2C19 inhibition, in which one free phenolic hydroxyl group and the pentyl side chain of CBD may play important roles.

Authors+Show Affiliations

Department of Hygienic Chemistry, Faculty of Pharmaceutical Sciences, Hokuriku University, Kanazawa, Japan.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

23318708

Citation

Jiang, Rongrong, et al. "Cannabidiol Is a Potent Inhibitor of the Catalytic Activity of Cytochrome P450 2C19." Drug Metabolism and Pharmacokinetics, vol. 28, no. 4, 2013, pp. 332-8.
Jiang R, Yamaori S, Okamoto Y, et al. Cannabidiol is a potent inhibitor of the catalytic activity of cytochrome P450 2C19. Drug Metab Pharmacokinet. 2013;28(4):332-8.
Jiang, R., Yamaori, S., Okamoto, Y., Yamamoto, I., & Watanabe, K. (2013). Cannabidiol is a potent inhibitor of the catalytic activity of cytochrome P450 2C19. Drug Metabolism and Pharmacokinetics, 28(4), 332-8.
Jiang R, et al. Cannabidiol Is a Potent Inhibitor of the Catalytic Activity of Cytochrome P450 2C19. Drug Metab Pharmacokinet. 2013;28(4):332-8. PubMed PMID: 23318708.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Cannabidiol is a potent inhibitor of the catalytic activity of cytochrome P450 2C19. AU - Jiang,Rongrong, AU - Yamaori,Satoshi, AU - Okamoto,Yasuka, AU - Yamamoto,Ikuo, AU - Watanabe,Kazuhito, Y1 - 2013/01/15/ PY - 2013/1/16/entrez PY - 2013/1/16/pubmed PY - 2014/4/30/medline SP - 332 EP - 8 JF - Drug metabolism and pharmacokinetics JO - Drug Metab Pharmacokinet VL - 28 IS - 4 N2 - The present study investigated the inhibitory effect of cannabidiol (CBD), a major constituent of marijuana, on the catalytic activity of cytochrome P450 2C19 (CYP2C19). (S)-Mephenytoin 4'-hydroxylase activities of human liver microsomes (HLMs) and recombinant CYP2C19 were inhibited by CBD in a concentration-dependent manner (IC₅₀ = 8.70 and 2.51 µM, respectively). Omeprazole 5-hydroxylase and 3-O-methylfluorescein O-demethylase activities in recombinant CYP2C19 were also strongly inhibited by CBD (IC₅₀ = 1.55 and 1.79 µM, respectively). Kinetic analysis for inhibition revealed that CBD showed a mixed-type inhibition against (S)-mephenytoin 4'-hydroxylation by recombinant CYP2C19. To clarify the structural requirements for CBD-mediated CYP2C19 inhibition, the effects of CBD-related compounds on CYP2C19 activity were examined. Olivetol inhibited the (S)-mephenytoin 4'-hydroxylase activity of recombinant CYP2C19 with the IC₅₀ value of 15.3 µM, whereas d-limonene slightly inhibited the activity (IC₅₀ > 50 µM). The inhibitory effect of CBD-2'-monomethyl ether (IC₅₀ = 1.88 µM) on CYP2C19 was comparable to that of CBD, although the inhibitory potency of CBD-2',6'-dimethyl ether (IC₅₀ = 14.8 µM) was lower than that of CBD. Cannabidivarin, possessing a propyl side chain, showed slightly less potent inhibition (IC₅₀ = 3.45 µM) as compared with CBD, whereas orcinol and resorcinol did not inhibit CYP2C19 activity at all. These results indicate that CBD caused potent CYP2C19 inhibition, in which one free phenolic hydroxyl group and the pentyl side chain of CBD may play important roles. SN - 1880-0920 UR - https://www.unboundmedicine.com/medline/citation/23318708/Cannabidiol_is_a_potent_inhibitor_of_the_catalytic_activity_of_cytochrome_P450_2C19_ L2 - http://joi.jlc.jst.go.jp/DN/JST.JSTAGE/dmpk/DMPK-12-RG-129?from=PubMed DB - PRIME DP - Unbound Medicine ER -