Slide 1: Phytocannabinoid DDIs and their clinical implications
Phytocannabinoid DDIs and their clinical implications Daniela Amaral Silva, PhD candidate Robert D. Clark, PhD Raimar Löbenberg, PhD
Slide 2: Pharmacology & Therapeutics (2020) 107621
Pharmacology & Therapeutics 215 (2020) 107621 Contents lists available at ScienceDirect Pharmacology & Therapeutics journal homepage: www.elsevier.com/locate/pharmthera Phytocannabinoid drug-drug interactions and their clinical implications Daniela Amaral Silva, David W. Pate >, Robert D. Clark ‘, N
Slide 3: Outline
1. Introduction 2. Phytocannabinoids chemistry and indications 3. Phytocannabinoids metabolic route Outline A. Reported in the literature B. Predicted by ADMET Predictor® 4. Potential DDIs involving phytocannabinoids 5. Conclusion
Slide 4: 1. Introduction
1. Introduction
Slide 5: Cannabis: Fiber, Food, Medicine or Narcotic?
Cannabis: Fiber, Food, Medicine or Narcotic? • What should you know about Cannabis?
Slide 6: Legal Cannabis in Canada
Legal Cannabis in Canada (G3) UNIVERSITY OF ALBERTA Gat E \@®) FACULTY OF PHARMACY AND uplifting the whole people PHARMACEUTICAL SCIENCES aa
Slide 7: Canada History
Canada History Drug prohibition in Canada began with the Opium Act of 1908, which prohibited the sale, manufacture, and importation of opium for other than medicinal use. This was followed by the Opium and Drug Act of 1911, which outlawed the sale or possession of morphine, opium, or cocaine. Cannab
Slide 8: USA
USA • Attorney General John Mitchell of the Nixon administration placed marijuana in Scheldule I category in 1972 as part of the ranking or “scheduling” of all drugs under the 1970 Controlled Substances Act. • Schedule I drugs are deemed to have no medical use and a high potential for abuse. • “In s
Slide 9: Marijuana is the most trafficked drug in the world
Marijuana is the most trafficked drug in the world • In Canada alone the illegal trade of marijuana reaps an estimated $7 billion in income annually for organized crime. • In addition, the administrative burden and social harms associated with the enforcement of marijuana laws, particularly for simp
Slide 10: Dioecious male and female plants
Dioecious male and female plants
Slide 11: Cannabis: The Plant
In his original 1753 Cannabis: The Plant classification, Carl Linnaeus identified just one, Cannabis sativa. The first indication of dissent came in 1785 when another eminent biologist, Jean-Baptiste Lamarck, was given some plant specimens collected in India. C indica The cannabis crop •Julie Gould
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Slide 13: 2. Phytocannabinoids chemistry and indications
2. Phytocannabinoids chemistry and indications
Slide 14: Two major chemical constituents: CBD and THC
Two major chemical constituents: CBD and THC OH O OH A CBD ase OH th Syn HO CO2 OH O HO CBDA OH CBD HO CBGA OH O TH OH Syn CA H H thas e H OH H O CO2 O THCA THC
Slide 15: Phytocannabinoid biosynthesis pathways
OH O OH O CO2 OH CBCA OH OH Synthase O HO CBGA CBCA HO THCA B DA se Synthase CBG C tha CO2 n Sy OH O OH H OH OH O H O OH O THCA CBC HO CBDA CO2 CO2 OH OH Oxidative H OH H degradation O O HO THC CBN CBD
Slide 16: Phytocannabinoids in fresh Cannabis
OH O OH O CO2 OH CBCA OH OH Synthase O HO CBGA • Terpenophenolic phytocannabinoids per se are not CBCA HO abundant in fresh Cannabis, theyTHCAare rather found as their DA e Synthase carboxy form (THCA CBG CB thasand CBDA) CO2 yn o Neither are Spsychoactive OH O OH o THC and CBD are a product of thei
Slide 17: THC, CBD, CBN, CBG indications
OH OH OH OH H H HO HO O O CBD THC CBN CBG • Non- • Psychoactive • Sedative • Anti- psychoactive • Pain management • Antibacterial inflammatory • Epidolex® • Antiemetic • Antibiotic o Epilepsy • Antispasmodic • Antifungal • Appetite stimulant • Sativex® (whole • Has been suggested plant extract) for
Slide 18: 3. Phytocannabinoids metabolic route
3. Phytocannabinoids metabolic route A. Reported in the literature
Slide 19: THCA
Dibenzopyran numbering system THCA Non-psychoactive and is not converted to THC in vivo Glucuronic acid conjugation Hydroxylation CYP at C8 CYP Hydroxylation at C11 11-hydroxy-Δ9-tetrahydrocannabinolic 8α-OH-THCA and 8β-OH- acid-A THCA (11-OH-THCA) CYP 11-nor-9-carboxy-Δ9-tetrahydrocannabinolic Main
Slide 20: THC
THC Epoxide at C9–10 followed by Hydroxylation at C8 followed hydrolysis or glutathione by dehydration CYP3A4 CYP3A4 conjugation. OH H Hydroxylation at C’1 to C’5 of the side chain H O Glucuronic acid conjugation Hydroxylation CYP2C9 at C11 MAJOR METABOLITE IN FECES 11-hydroxy-Δ9-tetrahydrocannabino
Slide 21: CBD
CBD 11 9 8 10 OH 1 7 2 2’ 4’ 13 HO 3 4 1’ 3’ 5’ 12 ENZYME METABOLITE CYP1A1 8a/b-OH-, 11-OH-, and 1’-OH-CBD CYP1A2 8a/b-OH-CBD, 1’-, 2’-, 3’-, and 4’-OH-CBD CYP2C19 8a-OH-, 11-OH-, and 4’-OH-CBD CYP2D6 8a/b-OH-CBD, 11-OH-, 4’-OH-, and 5’-OH-CBD CYP3A4 8a/b-OH-CBD, 11-OH-, 2’-OH-, 4’-OH-, and 5’-OH-C
Slide 22: CBC
OH Rank order of in vitro CBC R4 CBC metabolites R2 R6 R8 identified in mouse and R3 R9 O rabbit microsomes R1 R5 R7 METABOLITE R1 R2 R3 R4 R5 R6 R7 R8 R9 MOUSE RABBIT 1'-OH OH H H H H H H H H 8 - 2'-OH H OH H H H H H H H 4 - 5'-OH H H OH H H H H H H 1 1 6'-OH H H H OH H H H H H 2 4 1''-OH H H H H O
Slide 23: CBG
Rank order of in vitro CBG metabolites identified in liver microsomes from different 9’ animals OH CBG 5’ 1’ 7’ 3’ 8’ 6’ 4’ 2’ 2’’ 4’’ HO 1’’ 3’’ 5’’ METABOLITE MOUSE RAT GUINEA PIG RABBIT CAT 1''-OH 4 7 T 4 7 2''-OH - - 6 - - 3''-OH 7 6 2 5 6 4''-OH 2 4 5 3 3 5''-OH 4 7 T 4 7 4'-OH 3 3 3 5 5 8'-OH
Slide 24: 3. Phytocannabinoids metabolic route: B. Predicted by ADMET Predictor
3. Phytocannabinoids metabolic route B. Predicted by ADMET Predictor®
Slide 25: In silico predictions of CYP isoforms in phytocannabinoid metabolism
In silico predictions can be useful to suggest the role of CYP isoforms in phytocannabinoid metabolism à guidance for in vitro metabolism studies with recombinant human enzymes. Chemical Structures: THC, THCA, CBD, CBDA, CBC, CBCA, CBG ,CBGA, THCV and CBDV CYP CYP Inhibitor Substrate 5 CYP isoforms:
Slide 26: Predicted phytocannabinoid substrates of CYP isoforms
Predicted phytocannabinoid substrates of CYP isoforms by ADMET Predictor®. The percentages shown within parentheses represent the degree of confidence. CYP isoform THCA THC CBDA CBD CBCA CBC CBGA CBG THCV CBDV CYP1A2 No (97%) Yes (54%) No (97%) No (89%) No (66%) Yes (73%) No (89%) Yes (88%) Yes (67%
Slide 27: Predicted phytocannabinoid inhibitors of CYP isoforms
Predicted phytocannabinoid inhibitors of CYP isoforms by ADMET Predictor®. The percentages shown within parentheses represent the degree of confidence. CYP isoform THCA THC CBDA CBD CBCA CBC CBGA CBG THCV CBDV Yes No No No No No No No No No CYP1A2 (55%) (59%) (86%) (97%) (51%) (73%) (90%) (97%) (73%
Slide 28: BCRP OATP OCT2
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Slide 29: Cannabinoid metabolite structures and metabolizing enzymes
Cannabinoid Metabolite structure (highest yield) Metabolizing enzymes Observed 11-OH-THCA vs. THCA (CYP2C8);CYP2C9 Predicted only to be 19% (38%) 11-OH-THC CYP1A2;(CYP2A6);CYP2C9; vs. THC CYP2C19;CYP2D6;CYP3A4 Predicted only to be 9% (25%) CBD CYP2C9; CYP2D6 NA (23%) CYP1A2;(CYP2A6); CBC Accurate CY
Slide 30: 4. Potential DDIs involving phytocannabinoids
4. Potential DDIs involving phytocannabinoids
Slide 31: CYP-based pharmacokinetic drug interactions
Important PK drug-interactions are CYP-based, and can occur when a compound inhibits, induces or competes for a CYP isoform that metabolizes the other concomitantly administered drug. OH OH + O HO OH CYP s OH O H H isoform - O OH HO
Slide 32: Probable consequence of CYP inhibition based on in silico results
Probable consequence of CYP inhibition based on in silico results Probable Cytochrome Prototypical substrates# Inhibited by* consequence/ Recommendation Acetaminophen, haloperidol, CYP1A2 THCA theophylline, warfarin Amitriptyline, celecoxib, clopidogrel, THCA, THC, CBDA, CBD, Increased drug CYP2C9 f
Slide 33: THC pharmacodynamic and pharmacokinetic interactions
PHARMACODYNAMIC INTERACTIONS THC Concomitant Drug Amitriptyline, amoxapine, desipramine, other tricyclic Clinical Effect(s) Additive tachycardia, hypertension, drowsiness Recommendation Dose adjustment antidepressants Amphetamines, cocaine, other Additive hypertension, tachycardia, possibly Disconti
Slide 34: CBD is both a substrate and an inhibitor of CYP450 enzymes
CBD is both a substrate and an inhibitor of CYP450 enzymes • Hexobarbital (increased the bioavailability and elimination half-time) (Dose: 600mg/day). • Clobazam (increased plasma level by 60%, and the level of its active metabolite (norclobazam) by 500%. (5 mg/kg/day - titrating up until 25 mg/kg/d
Slide 35: DDI is not only about metabolizing enzymes
DDI is not only about metabolizing enzymes… What about: Pharmacodynamic interactions? Protein binding/ displacement? Effects on gastric motility? Transporters inhibition?
Slide 36: Fatty acid binding protein - FABP
Fatty acid binding protein - FABP • The most prevalent hepatic binding/chaperone protein with a broad specificity for multiple lipidic ligands and xenobiotics. • Phytocannabinoids are highly lipophilic molecules - cytoplasmic transport? • Phase I and Phase II enzymes à Endoplasmic Reticulum of hepat
Slide 37: Clinically significant inhibitory effects cannot be ruled out entirely
Clinically significant inhibitory effects cannot be ruled out entirely…. • Is there substantial clinical risk? • More specific human data is needed • What about the dose at which phytocannabinoids are used in the clinic? • Is it high enough for the blood plasma concentration to reach Ki and/or IC50
Slide 38: Conclusions
Conclusions • Understanding of phytocannabinoid metabolism is a key factor within the drug development process to reduce the risk of costly late-stage project failure due to adverse ADMET properties. • With the increased widespread use of legal marijuana (medically and recreationally), DDI knowledge
Slide 39: Thank you! Questions?
Thank you! Questions? (3) UNIVERSITY OF ALBERTA ons » @) FACULTY OF PHARMACY AND Rae whole people PHARMACEUTICAL SCIENCES