Original article found here
Cannabis; cannabinoids; THC; CBD; drug–drug interactions; pharmacokinetic; cytochrome P450; UDP-glucuronosyltransferases; glycoprotein p; BCRP; MRPs
2. Potential Drug Interactions
3. Effects of Cannabis on Drug Metabolizing Enzymes and Related Drug Interactions
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|Cannabinoid Based Treatment and Interactions||Affected Transporters and/or Metabolic Enzymes||Experimental Results, Notes and Outcomes||References|
|Cannabis, THC, CBD, CBN with either chemotherapies, abuse drugs or medications||-Membrane transporters ABC super family (glycoprotein P; P-gp, Breast cancer-resistance protein; BCRP, and multidrug resistance protein; MRP1, 2, 3 and 4)
-Cytochrome P450 (3A, 2D6, 2C9, 1A1, 1A2, 1B1, 2B6 and 2C8)
|–P-gp, BCRP, and MRP1-4 transporters expression were dysregulated by cannabinoids, but in higher concentrations than that usually measured in cannabis smokers.
–CYP3A was competitively inhibited by THC, CBD and CBN, with CBD being the most potent in a concentration compatible with that in usual cannabis inhalation.
–CYP2D6 was inhibited by THC, CBD and CBN, with CBD being the most potent in a higher concentration than that in usual cannabis consumption.
–CYP2C9 was inhibited by THC, CBD and CBN, with CBD inhibitory effect being dependent on the used substrates.
–CYP1A1, 1A2, 1B1, 2B6, 2C19, 3A4 and 2C8 were strongly inhibited by CBD.
–UGT1A9, and 2B7 were inhibited by CBD.
–UGT1A7, 1A8, and 1A9 were inhibited by CBN.
–UGT2B7 was activated by CBN.
|Δ9-THC, CBD and marijuana inhalation with psychotropic agents||-Cytochrome P450||–CYP2C9 and CYP3A4 were inhibited by Δ9-THC.
–CYP2C19 and CYP3A4 were inhibited by CBD.
–CYP1A1 and CYP1A2 were induced by marijuana inhalation.
|Cannabinoids on other drugs||Cytochrome P450||–CYP3A4 inhibitors and stimulators affect the elimination of Δ9-THC and CBD.
|CBD with antiepileptic drugs||Cytochrome P450 or unknown||Clinical studies of DDI:
-Non-significant increase of the clobazam plasma level administered with CBD (n = 13 children) due to potent inhibition of CYP2C19.
-Significant change of plasma level of N-desmethylclobazam by CBD co-administration while no significant change in the level of valproate, stiripentol and levetiracetam (n = 24 open label trial).
-All patients showed significant changes of the plasma levels of clobazam, N-desmethylclobazam, rufinamide, and topiramate by increasing CBD doses. The mean therapeutic range was exceeded for clobazam and N-desmethylclobazam; the plasma levels of eslicarbazepine and zonisamide were increased in adults only (n = 39 adults and 42 children).
|Synthetic and Phyto-cannabinoids||-Cytochrome P450
|–CYP1A catalysed MROD activity was weakly inhibited by MAM-2201, JWH-019, STS-135, and UR-144.
–CYP2C8 catalysed amodiaquine N-deethylase was strongly inhibited by AM-2201, MAM-2201, and EAM-2201.
–CYP2C9 catalysed diclofenac hydroxylation and CYP3A-catalyzed midazolam 1′-hydroxylation were inhibited by AM-2201 and MAM-2201.
–CYP2C9 catalysed diclofenac 4′-hydroxylation, CYP2C19-catalyzed [S] -mephenytoin 4′-hydroxylation, and CYP3A-catalyzed midazolam 1′ hydroxylation were strongly inhibited by EAM-2201 (time-dependent inhibition).
–CYP2B6 and CYP2C9 were strongly inhibited by THC, CBN and CBD.
–CYP2A6 was inhibited by THC and CBN (mechanism-based inhibition).
–CYP2D6 was competitively inhibited by CBD.
–CYP1A1 mRNA expression was increased by THC in Hepa-1 cells, but EROD activity in CYP1A1 supersomes was inhibited by THC.
–CYP1A1, CYP1A2, and CYP1B1 were strongly inhibited by CBD (mechanism-based inhibition).
–CYP3A was inhibited by CBD in human liver microsomes.
–CYP2C19-catalyzed [S] -mephenytoin hydroxylation was inhibited by (CBD and THC (Mixed-type inhibition).
–UGT1A9– and UGT2B7 catalysed ethanol glucuronidation were non-competitively inhibited by CBD, and unlike the inclined ethanol glucuronidation in human liver microsome by CBN (dose dependent).
–UGT1A3 catalysed chenodeoxycholic acid 24-acylglucuronidation was strongly competitively inhibited by AM-2201, MAM-2201, and EAM-2201.
–UGT2B7-mediated naloxone 3β-D-glucuronidation was competitively inhibited by AM-2201.
4. Other Potential Drug Interactions
Conflicts of Interest
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