Cytochromes P450 (CYPs) are a superfamily of proteins which in the human body are responsible of the metabolism of endogenous and exogenous chemicals, including cannabinoids. CYPs metabolize drugs mainly in the liver, making them specially relevant when cannabinoids are used through the oral route of administration. cannabinoids are metabolized by CYPs but they can also induce (increase activity) or inhibit the action of CYPs, modulating their metabolic action in other drugs. Co-administration of cannabinoids and other drugs can modulate their levels in blood, affecting their therapeutic properties. More research is needed to understand how cannabinoids interact with other drugs.

Phytocannabinoids: 
Literature Discussion: 

General cytochrome p450 information

Cyp450 catalyzes the oxygenation of lipophilic drugs/substances making these more hydrophilic.

Cyp450 subfamily 1-3 are predominantly involved in the metabolism of xenobiotics/commercial drugs (reviewed in: Ma and Lu, 2011).

Cyp450 subfamily 4 and higher are predominantly involved in the metabolism of endogenous substances such as fatty acids, steroids and endocannabinoids (Fer et al., 2008).

The most important human cyp450’s are:

  • Cyp2D6:
    • Metabolizes ±25% of all drugs on the market
      • Beta blocker
      • Anti-depressant
      • Anti-arrhythmic
      • Anti-psychotic
      • Tamoxifen (ER+ Breast Cancer)
    • Multiple alleles
      • Poor metabolizers
        • Cyp2D6*3, -4, -5 and -6
        • 5-10% White
        • 1-2% Chinese/Japanese
        • Enzyme inactive, high drug levels
      • Intermediate metabolizers
        • Cyp2D6*9, -10, -41
        • Low enzyme activity
      • Extensive metabolizers
        • Normal enzyme activity
      • Ultra-rapid metabolizers
        • Multiple copies of Cyp2D6
        • 1-2% White
        • 30% Ethiopian
        • High enzyme activity, low drug levels
  • Cyp2C9:
    • Metabolizes several common drugs
      • Hypoglycemic (tolbutamide, glipizide)
      • Anti-convulsant (phenytoin)
      • Anti-coagulant (warfarin)
      • Anti-inflammatory (flurbiprofen)
    • Over 30 polymorphisms/alleles
      • Poor metabolizers
        • Cyp2C9*2 and -3
        • 0.4% (Cyp2C9*3) to 1% (Cyp2C9*2) White
        • Very low frequency in Asian populations
        • Low enzyme activity, high drug levels
      • Intermediate metabolizers
        • Cyp2C9*1
        • Normal enzyme activity
  • Cyp2C19:
    • Metabolizes several common drugs
      • Anti-convulsant ((S-)mephenytoin)
      • Anti-ulcerant (omeprazole)
      • Anxiolytic (diazepam)
    • Over 20 polymorphisms/alleles
      • Poor metabolizers
        • Cyp2C19*2 and -3
        • 5% White
        • 15-25% Chinese, Japanese and Korean
        • Enzyme inactive, high drug levels
      • Extensive metabolizers
        • Low drug levels
  • Cyp3A4:
    • Metabolizes over 50% of commercial drugs
    • Over 20 polymorphisms/alleles
      • Cyp3A4*2 and -7 prominent in White people
      • Cyp3A4*16 and -18 prominent in Asian people
      • Extensive functional redundancy with Cyp3A5
  • Cyp3A5:
    • Multiple alleles
    • Functional enzymes in:
      • 25% of White people
      • 50% of Black people
    • Cyp3A4*1 has normal enzyme activity
    • Cyp3A4*3 has no enzyme activity

For a full overview of human CYP450 alleles/polymorphisms, please see: http://www.cypalleles.ki.se/

For a full overview of drug interactions with the major CYP450 alleles, please see: http://medicine.iupui.edu/CLINPHARM/ddis/main-table

Interactions between cannabinoids and cytochrome P450 enzymes

Most THC (and presumably most plant cannabinoids) is degraded by Cyp2C9 in the liver.

Vice versa, most cannabinoids and CBD in particular have the ability to inhibit Cyp enzymes to varying degrees.

As Cyp enzymes are not only responsible for the metabolism of cannabinoids but also of all medical drugs and many components of our general metabolism these cannabinoid-Cyp interactions can have a large impact on our metabolism and well being.

Given the amount of circulating cannabinoids, typically nanomolar, and their apparent affinity for Cyp enzymes, typically low-micromolar, cannabinoids are normally not expected to exert a strong effect on other metabolic events. However, Cyp enzymes are highly polymorphic with multiple alleles in the general population, each with slightly different functional characteristics. Such polymorphisms do not only help determine which diseases a person is likely to develop but also how they respond to cannabinoids and/or other therapeutic drugs.

For instance, although CBD is a relatively strong inhibitor of Cyp2D6, this effect probably occurs at relatively high doses (200mg or higher, estimated from: (Yamaori et al., 2011)).

The information in the table above is derived from:

Fer, M., Corcos, L., Dréano, Y., Plée-Gautier, E., Salaün, J.-P., Berthou, F., and Amet, Y. (2008). Cytochromes P450 from family 4 are the main omega hydroxylating enzymes in humans: CYP4F3B is the prominent player in PUFA metabolism. J. Lipid Res. 49, 2379–2389.

Gaston, T.E., and Friedman, D. (2017). Pharmacology of cannabinoids in the treatment of Epilepsy. Epilepsy Behav. EB 70, 313–318.

Hryhorowicz, S., Walczak, M., Zakerska-Banaszak, O., Słomski, R., and Skrzypczak-Zielińska, M. (2017). Pharmacogenetics of cannabinoids. Eur. J. Drug Metab. Pharmacokinet.

Huestis, M.A. (2007). Human cannabinoid Pharmacokinetics. Chem. Biodivers. 4, 1770–1804.

Jiang, R., Yamaori, S., Takeda, S., Yamamoto, I., and Watanabe, K. (2011). Identification of cytochrome P450 enzymes responsible for metabolism of cannabidiol by human liver microsomes. Life Sci. 89, 165–170.

Jiang, R., Yamaori, S., Okamoto, Y., Yamamoto, I., and Watanabe, K. (2013). Cannabidiol is a potent inhibitor of the catalytic activity of cytochrome P450 2C19. Drug Metab. Pharmacokinet. 28, 332–338.

Ma, Q., and Lu, A.Y.H. (2011). Pharmacogenetics, pharmacogenomics, and individualized medicine. Pharmacol. Rev. 63, 437–459.

Stott, C., White, L., Wright, S., Wilbraham, D., and Guy, G. (2013). A Phase I, open-label, randomized, crossover study in three parallel groups to evaluate the effect of Rifampicin, Ketoconazole, and Omeprazole on the pharmacokinetics of THC/CBD oromucosal spray in healthy volunteers. SpringerPlus 2, 236.

Yamaori, S., Okamoto, Y., Yamamoto, I., and Watanabe, K. (2011). Cannabidiol, a major phytocannabinoid, as a potent atypical inhibitor for CYP2D6. Drug Metab. Dispos. Biol. Fate Chem. 39, 2049–2056.

Yamaori, S., Koeda, K., Kushihara, M., Hada, Y., Yamamoto, I., and Watanabe, K. (2012). Comparison in the In Vitro Inhibitory Effects of Major Phytocannabinoids and Polycyclic Aromatic Hydrocarbons Contained in Marijuana Smoke on Cytochrome P450 2C9 Activity. Drug Metab. Pharmacokinet. 27, 294–300.

Yamaori, S., Okushima, Y., Masuda, K., Kushihara, M., Katsu, T., Narimatsu, S., Yamamoto, I., and Watanabe, K. (2013). Structural requirements for potent direct inhibition of human cytochrome P450 1A1 by cannabidiol: role of pentylresorcinol moiety. Biol. Pharm. Bull. 36, 1197–1203.

Yamaori, S., Kinugasa, Y., Jiang, R., Takeda, S., Yamamoto, I., and Watanabe, K. (2015). Cannabidiol induces expression of human cytochrome P450 1A1 that is possibly mediated through aryl hydrocarbon receptor signaling in HepG2 cells. Life Sci. 136, 87–93.

 

Metabolites: