המדריך המלא להתנגשויות בין תרופתיות ו-CBD

APPENDIX A: GLOSSARY
Allosteric modulation
A type of protein-chemical interaction. An allosteric modulator changes the shape of the protein, which alters how well another chemical would fit.
Anandamide
The first known endocannabinoid. Discovered by Devane et. al. in 1992.
Cannabidiol (CBD)
A major non-intoxicating plant cannabinoid with significant anti-epileptic and anti-inflammatory properties.

7-carboxy-cannabidiol (7-COOH-CBD)
A major metabolite of CBD which bears some chemical resemblance to the antiepileptic drug valproate.

6alpha-hydroxy-cannabidiol (6α-OH-CBD)
A minor metabolite of CBD formed when CBD is oxidized by CYPs 3A4, 3A5, 2D6, and 2C19.

Cannabidivarin (CBDV)
A minor plant cannabinoid that has been studied for the treatment of epilepsy and autism-spectrum disorders.

Cannabinol (CBN)
An ostensibly non-psychoactive cannabinoid that is formed when THC degrades in sunlight or heat.
Competitive inhibition

A type of protein-chemical interaction wherein the chemical sits in the active site of the protein, preventing other chemicals from entering.

Cytochrome P450 (CYP)
An important family of enzymes that is involved in metabolizing many pharmaceuticals and endogenous compounds.

Epidiolex
A pharmaceutical formulation of nearly pure CBD that is applied as a sublingual spray.

Induction
A process whereby the activity of an enzyme is increased. Genetic induction refers to changes in gene expression that increase the cell’s production of the enzyme

Ki
A measure of the strength of protein-ligand binding. In this piece, the Ki indicates the potency with which cannabinoids inhibit CYPs, normalized to the experimental conditions of the study.

Marinol
A pharmaceutical formulation of nearly pure THC. Approved by the FDA for treating cancer- and AIDS-related health problems.

Polycyclic aromatic hydrocarbons (PAHs) A class of compounds produced in smoke, whether from cannabis, tobacco, or wood fires.

Prodrug
A drug whose metabolites are the primary active compounds.

Sativex
A pharmaceutical cannabis extract with a 1:1 ratio of CBD to THC. Approved in many countries outside of the United States

Terpenes
Volatile hydrocarbon compounds produced by plants. They are responsible for the smells associated with many plants.

Tetrahydrocannabinol (THC)
The major intoxicating plant cannabinoid. It causes a high, alleviates pain, reduces nausea, and is being investigated for numerous other medical conditions.

11-hydroxy-tetrahydrocannabinol (11-OH-THC)
Major metabolite of THC. It appears to be more psychoactive than THC itself. It’s primarily created by CYP2C9-dependent metabolism of THC.

11-nor-9-carboxy-tetrahydrocannabinol (11-COOH-THC)
Major excreted metabolite of THC. It is not psychoactive, and is primarily created by CYP3A4-dependent metabolism of 11-OH-THC.

Tetrahydrocannabivarin
A minor plant cannabinoid that has been studied for the treatment of some metabolic and addictive disorders.

APPENDIX B: KI TABLE

Table of Ki values for cannabinoids’ inhibition of various CYP enzymes. The Ki provides an indication of the potency of inhibition, with smaller Kis implying a smaller dose is necessary to cause CYP inhibition. The Kis are best used to understand the relative potency of CYP inhibition. The Ki only suggests the dose of a cannabinoid that causes

inhibition—it does not indicate the duration of the effect. It also depends on the second drug used to measure CYP activity.

All numbers are Kis in μM.
† Cannabinoid was a more potent inhibitor when given before the second drug.

* Ki not calculated. Potency notably lower than CBD’s potency.

** Only caused induction, not inhibition. In these studies, a fixed dose of 120 mg/kg was used.

^ The upper bound came from an experiment with a deceased human’s liver, which may have had a polymorphism in the CYP2C9 gene. The lower bound used purified enzyme

Figure of five common plant cannabinoids. The “pentylresorcinol” or “olivitol” moiety is highlighted in red. Both the free hydroxyls as well as the 5-carbon chain contribute to inhibition of most CYPs, although olivetol on its own is a much weaker inhibitor

SOURCES

1. Abrams, D. I., Couey, P., Shade, S. B., Kelly, M. E. & Benowitz, N. L. Cannabinoidopioid interaction in chronic pain. Clin. Pharmacol. Ther. 90, 844–851 (2011).
2. Alper, B. S., Manheimer, E. W. & Ehrlich, A. Point-of-care application: ‘Trial of cannabidiol for drug-resistant seizures in the Dravet syndrome’. Eur. J. Integr. Med. 14, 20–21 (2017).
3. Askari, A., Thomson, S. J., Edin, M. L., Zeldin, D. C. & Bishop-Bailey, D. Roles of the epoxygenase CYP2J2 in the endothelium. Prostaglandins Other Lipid Mediat. 107, 56–63 (2013).
4. Austin, C. A., Shephard, E. A., Pike, S. F., Rabin, B. R. & Phillips, I. R. The effect of terpenoid compounds on cytochrome P-450 levels in rat liver. Biochem. Pharmacol. 37, 2223–2229 (1988).
5. Bland, T. M., Haining, R. L., Tracy, T. S. & Callery, P. S. CYP2C-catalyzed delta(9)- tetrahydrocannabinol metabolism: Kinetics, harmacogenetics and interaction with phenytoin. Biochem. Pharmacol. 70, 1096–1103 (2005).
6. Bornheim, L. M., Everhart, E. T., Li, J. & Correia, M. a. Induction and genetic regulation of mouse hepatic cytochrome P450 by cannabidiol. Biochem. Pharmacol. 48, 161–71 (1994).
7. Borys, H. K., Ingall, G. B. & Karler, R. Hexobarbitone sleeping time caused by cannabidiol. 93–101 (1979).
8. Cesamet (nabilone) [package insert] Meda Pharmaceuticals Inc. https://www.cesamet.com/pdf/Cesamet_PI_50_count.pdf
9. Cheng, X. & Klaassen, C. D. Perfluorocarboxylic acids induce cytochrome P450 enzymes in mouse liver through activation of PPAR-α and CAR transcription factors. Toxicol. Sci. 106, 29–36 (2008).
10. Costa, B., Parolaro, D. & Colleoni, M. Chronic treatment with the endocannabinoid anandamide increases cytochrome P450 metabolizing system in the rat. Eur. J. Pharmacol. 449, 61–69 (2002).
11. De Petrocellis, L. et al. Effects of cannabinoids and cannabinoid-enriched Cannabis extracts on TRP channels and endocannabinoid metabolic enzymes. Br. J. Pharmacol. 163, 1479–1494 (2011).
12. De-Oliveira, A. C. A. X., Ribeiro-Pinto, L. F. & Paumgartten, F. J. R. In vitro inhibition of CYP2B1 monooxygenase by β-myrcene and other monoterpenoid compounds. Toxicol. Lett. 92, 39–46 (1997).
13. Devinsky, O. et al. Randomized, dose-ranging safety trial of cannabidiol in Dravet syndrome. Neurology (2018).
14. Egnell, A.-C., Houston, J. B. & Boyer, C. S. Predictive models of CYP3A4 Heteroactivation: in vitro-in vivo scaling and pharmacophore modeling. J. Pharmacol. Exp. Ther. 312, 926–937 (2005).
15. Gallily, R., Yekhtin, Z. & Hanuš, L. O. Overcoming the Bell-Shaped Dose-Response of Cannabidiol by Using Cannabis Extract Enriched in Cannabidiol. Pharmacol. & Pharm. 06, 75–85 (2015).
16. Gaston, T. E., Bebin, E. M., Cutter, G. R., Liu, Y. & Szaflarski, J. P. Interactions between cannabidiol and commonly used antiepileptic drugs. Epilepsia 58, 1586–1592 (2017).
17. Geffrey, A. L., Pollack, S. F., Bruno, P. L. & Thiele, E. A. Drug-drug interaction between clobazam and cannabidiol in children with refractory epilepsy. Epilepsia 56, 1246– 1251 (2015).
18. Grayson, L., Vines, B., Nichol, K. & Szaflarski, J. P. An interaction between warfarin and cannabidiol, a case report. Epilepsy Behav. Case Reports 9, 10–11 (2018).
19. Grotenhermen, F. Pharmacokinetics and pharmacodynamics of cocaine. J. Anal. Toxicol. 42, 327–360 (2003).
20. Guengerich, F. P. Cytochrome P450 and Chemical Toxicology. Chem. Res. Toxicol. 21, 70–83 (2008).
21. Jiang, R., Yamaori, S., Okamoto, Y., Yamamoto, I. & Watanabe, K. Cannabidiol Is a Potent Inhibitor of the Catalytic Activity of Cytochrome P450 2C19. Drug Metab. Pharmacokinet. 28, 332–338 (2013).
22. Jiang, R., Yamaori, S., Takeda, S., Yamamoto, I. & Watanabe, K. Identification of cytochrome P450 enzymes responsible for metabolism of cannabidiol by human liver microsomes. Life Sci. 89, 165–170 (2011).
23. Jones, G. & Pertwee, R. G. A metabolic interaction in vivo between cannabidiol and Δ1‐tetrahydrocannabinol. Br. J. Pharmacol. 45, 375–377 (1972).
24. Klein, C. et al. Cannabidiol potentiates Δ 9-tetrahydrocannabinol (THC) behavioural effects and alters THC pharmacokinetics during acute and chronic treatment in adolescent rats. Psychopharmacology. 218, 443–457 (2011).
25. Kosel, B. W. et al. The effects of cannabinoids on the pharmacokinetics of indinavir and nelfinavir. Aids 16, 543–550 (2002).
26. Manini, A. F. et al. Safety and pharmacokinetics of oral Cannabidiol when administered concomitantly with intravenous Fentanyl in humans. J. Addict. Med. 9, 204–210 (2015).
27. Nallathambi, R. et al. Identification of Synergistic Interaction Between Cannabis- Derived Compounds for Cytotoxic Activity in Colorectal Cancer Cell Lines and Colon Polyps That Induces Apoptosis-Related Cell Death and Distinct Gene Expression. Cannabis Cannabinoid Res. 3, 120–135 (2018).
28. Node, K. et al. Anti-inflammatory properties of Cytochrome P450 Epoxygenase- Derived Eicosanoids. Science (80). 285, 1276–1279 (1999).
29. Persson, A. et al. Decreased hippocampal volume and increased anxiety in a transgenic mouse model expressing the human CYP2C19 gene. Mol. Psychiatry 19, 733–741 (2014).
30. Sachse-Seeboth, C. et al. Interindividual variation in the pharmacokinetics of Δ9- tetrahydrocannabinol as related to genetic polymorphisms in CYP2C9. Clin. Pharmacol. Ther. 85, 273–276 (2009).
31. Shehab N, Sperling LS, Kegler SR & Budnitz DS. National estimates of emergency department visits for hemorrhage-related adverse. Arch. Intern. Med. 170, 1926– 1933 (1926).
32. Thomas, M. et al. Direct transcriptional regulation of human hepatic cytochrome P450 3A4 (CYP3A4) by peroxisome proliferator-activated receptor alpha (PPARa). Mol. Pharmacol. 83, 709–718 (2013).
33. Tolbert, D., Bekersky, I., Chu, H. M. & Ette, E. I. Drug-metabolism mechanism: Knowledge-based population pharmacokinetic approach for characterizing clobazam drug-drug interactions. J. Clin. Pharmacol. 56, 365–374 (2016).
34. Ujváry, I. & Hanuš, L. Human Metabolites of Cannabidiol: A Review on Their Formation, Biological Activity, and Relevance in Therapy. Cannabis Cannabinoid Res. 1, 90–101 (2016).
35. Vandrey, R. et al. Pharmacokinetic profile of oral cannabis in humans: Blood and oral fluid disposition and relation to pharmacodynamic outcomes. J. Anal. Toxicol. 41, 83–99 (2017).
36. Villard, P. H. et al. CYP1A1 induction in the colon by serum: Involvement of the PPARα pathway and evidence for a new specific human PPREα site. PLoS One 6,2–9 (2011).
37. Watanabe, K., Yamaori, S. , Jiang, R.,Kinugasa, Y., Okushima, Y, & Yamamoto I. et al.Inducibility of CYP enzymes by cannabidiol. Presented at the 2015 International Cannabinoid Research society. Talk #7
38. Watanabe, K., Yamaori, S., Nagata, Y., Usami, N., Okazaki, H. & Aramaki, H. et al. Metabolic interactions of major phytocannabinoids with human CYP2J2 enzyme. Presented at the 2017 International Cannabinoid Research Society. Poster #P3-14
39. Witsch, H. & Saint-Francois, B. Enhanced Activity of Benzpyrene Hydroxylase in Rat Liver and Lung After Acute Cannabis Administration. Toxicol. Appl. Pharmacol. 165–168 (1972).
40. Yamaori, S., Okushima, Y., Yamamoto, I. & Watanabe, K. Characterization of the structural determinants required for potent mechanism-based inhibition of human cytochrome P450 1A1 by cannabidiol. Chem. Biol. Interact. 215, 62–68 (2014).
41. Yamaori, S., Ebisawa, J., Okushima, Y., Yamamoto, I. & Watanabe, K. Potent inhibition of human cytochrome P450 3A isoforms by cannabidiol: Role of phenolic hydroxyl groups in the resorcinol moiety. Life Sci. 88, 730–736 (2011a).
42. Yamaori, S. et al. 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 (2015).
43. Yamaori, S. et al. 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 (2012).
44. Yamaori, S., Kushihara, M., Yamamoto, I. & Watanabe, K. Characterization of major phytocannabinoids, cannabidiol and cannabinol, as isoform-selective and potent inhibitors of human CYP1 enzymes. Biochem. Pharmacol. 79, 1691–1698 (2010).
45. Yamaori, S., Maeda, C., Yamamoto, I. & Watanabe, K. Differential inhibition of human cytochrome P450 2A6 and 2B6 by major phytocannabinoids. Forensic Toxicol. 29, 117–124 (2011b).
46. Yamaori, S., Okamoto, Y., Yamamoto, I. & Watanabe, K. Cannabidiol, a major phytocannabinoid, as a potent atypical inhibitor for CYP2D6. Drug Metab. Dispos. 39, 2049–2056 (2011c).
47. Yamaori, S. et al. Structural Requirements for Potent Direct Inhibition of Human Cytochrome P450 1A1 by Cannabidiol: Role of Pentylresorcinol Moiety. Biol. Pharm. Bull. 36, 1197–203 (2013).
48. Zanger, U. M. & Schwab, M. Cytochrome P450 enzymes in drug metabolism: Regulation of gene expression, enzyme activities, and impact of genetic variation. Pharmacol. Ther. 138, 103–141 (2013)