Cannabis (Cannabis sativa)
Predicting the Potential for Cannabinoids to Precipitate Pharmacokinetic Drug Interactions via Reversible Inhibition or Inactivation of Major Cytochromes P450 CSV JSON

Cannabis constituents, CBD and THC, have been known to inhibit or inactive CYP450 enzymes. The binding-corrected reversible (IC50,u) and irreversible inhibition potency (KI,u) values were determined for CBD and THC. A combined mechanistic static model showed a moderate-strong interaction between CBD and drugs metabolized via CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A. The model also showed an interaction between THC and CYP1A2, CYP2C9, and CYP3A.

Cannabis (Cannabis sativa)

32587099

1 . 11-OH-THC Inhibition on CYP2D6 (id=NPDI-7DFm1w)

In Vitro Enzyme Inhibition Experiment

Inhibition was detected.  Cutoff used —

Table 1 lists the oral and inhalational doses and estimated maximum plasma concentrations of CBD, THC, and THC metabolites used for predicting the magnitude of pharmacokinetic cannabinoid-drug interactions. 

dextromethorphan 1119510

11-hydroxy-delta-9-tetrahydrocannabinol

dextrorphan 4349487

  • CYP2D6 4173631

Cell fraction Pooled human liver microsomes -7999662

Results

Sample Compound measured Value Measurement Study sequence Additional information N replicates

Experimental Conditions

0.1 mg/ml

Commercially available

5 µM

2 . CBD Inhibition on CYP2D6 (id=NPDI-uDdXhQ)

In Vitro Enzyme Inhibition Experiment

Inhibition was detected.  Cutoff used —

CBD was predicted to precipitate strong drug interactions (AUCR greater than or equal to 5) mediated by CYP2C9, 2C19, and 3A and moderate drug interactions (AUCR between 1.2 and 5) mediated by CYP1A2 and 2D6 based on the AUCR cutoffs recommended by the FDA (https://www.fda.gov/media/134582/ download). 

Table 1 lists the oral and inhalational doses and estimated maximum plasma concentrations of CBD, THC, and THC metabolites used for predicting the magnitude of pharmacokinetic cannabinoid-drug interactions. 

dextromethorphan 1119510

cannabidiol

dextrorphan 4349487

  • CYP2D6 4173631

Cell fraction Pooled human liver microsomes -7999662

Results

Sample Compound measured Value Measurement Study sequence Additional information N replicates

Experimental Conditions

0.1 mg/ml

Commercially available

5 µM

3 . THC Inhibition on CYP2D6 (id=NPDI-MQ0Xtw)

In Vitro Enzyme Inhibition Experiment

Inhibition was detected.  Cutoff used —

Table 1 lists the oral and inhalational doses and estimated maximum plasma concentrations of CBD, THC, and THC metabolites used for predicting the magnitude of pharmacokinetic cannabinoid-drug interactions. 

dextromethorphan 1119510

delta-9-tetrahydrocannabinol

dextrorphan 4349487

  • CYP2D6 4173631

Cell fraction Pooled human liver microsomes -7999662

Results

Sample Compound measured Value Measurement Study sequence Additional information N replicates

Experimental Conditions

0.1 mg/ml

Commercially available

5 µM

4 . 11-OH-THC Inhibition of CYP2C9 (id=NPDI-KEwGCg)

In Vitro Enzyme Inhibition Experiment

Inhibition was detected.  Cutoff used —

Table 1 lists the oral and inhalational doses and estimated maximum plasma concentrations of CBD, THC, and THC metabolites used for predicting the magnitude of pharmacokinetic cannabinoid-drug interactions. 

diclofenac 1124300

11-hydroxy-delta-9-tetrahydrocannabinol

4'-hydroxydiclofenac

  • CYP2C9 4309227

Cell fraction Pooled human liver microsomes -7999662

Results

Sample Compound measured Value Measurement Study sequence Additional information N replicates

Experimental Conditions

0.5 mg/ml

Commercially available

5 µM

5 . CBD Inhibition of CYP2C9 (id=NPDI-IhJ2pQ)

In Vitro Enzyme Inhibition Experiment

Inhibition was detected.  Cutoff used —

CBD was predicted to precipitate strong drug interactions (AUCR greater than or equal to 5) mediated by CYP2C9, 2C19, and 3A and moderate drug interactions (AUCR between 1.2 and 5) mediated by CYP1A2 and 2D6 based on the AUCR cutoffs recommended by the FDA (https://www.fda.gov/media/134582/ download). 

diclofenac 1124300

cannabidiol

4'-hydroxydiclofenac

  • CYP2C9 4309227

Cell fraction Pooled human liver microsomes -7999662

Results

Sample Compound measured Value Measurement Study sequence Additional information N replicates

Experimental Conditions

0.1 mg/ml

Commercially available

5 µM

6 . THC Inhibition of CYP2C9 (id=NPDI-gvjqdw)

In Vitro Enzyme Inhibition Experiment

Inhibition was detected.  Cutoff used —

Table 1 lists the oral and inhalational doses and estimated maximum plasma concentrations of CBD, THC, and THC metabolites used for predicting the magnitude of pharmacokinetic cannabinoid-drug interactions. 

diclofenac 1124300

delta-9-tetrahydrocannabinol

4'-hydroxydiclofenac

  • CYP2C9 4309227

Cell fraction Pooled human liver microsomes -7999662

Results

Sample Compound measured Value Measurement Study sequence Additional information N replicates

Experimental Conditions

0.5 mg/ml

Commercially available

5 µM

7 . 11-OH-THC Inhibition on CYP2C19 (id=NPDI-kU7TmQ)

In Vitro Enzyme Inhibition Experiment

Inhibition was detected.  Cutoff used —

Table 1 lists the oral and inhalational doses and estimated maximum plasma concentrations of CBD, THC, and THC metabolites used for predicting the magnitude of pharmacokinetic cannabinoid-drug interactions. 

omeprazole

11-hydroxy-delta-9-tetrahydrocannabinol

5-hydroxyomeprazole

  • CYP2C19 4311137

Cell fraction Pooled human liver microsomes -7999662

Results

Sample Compound measured Value Measurement Study sequence Additional information N replicates

Experimental Conditions

0.1 mg/ml

Commercially available

10 µM

8 . CBD Inhibition on CYP2C19 (id=NPDI-2YTaDQ)

In Vitro Enzyme Inhibition Experiment

Inhibition was detected.  Cutoff used —

CBD was predicted to precipitate strong drug interactions (AUCR greater than or equal to 5) mediated by CYP2C9, 2C19, and 3A and moderate drug interactions (AUCR between 1.2 and 5) mediated by CYP1A2 and 2D6 based on the AUCR cutoffs recommended by the FDA (https://www.fda.gov/media/134582/ download). 

Table 1 lists the oral and inhalational doses and estimated maximum plasma concentrations of CBD, THC, and THC metabolites used for predicting the magnitude of pharmacokinetic cannabinoid-drug interactions. 

omeprazole

cannabidiol

5-hydroxyomeprazole

  • CYP2C19 4311137

Cell fraction Pooled human liver microsomes -7999662

Results

Sample Compound measured Value Measurement Study sequence Additional information N replicates

Experimental Conditions

0.1 mg/ml

Commercially available

10 µM

9 . THC Inhibition on CYP2C19 (id=NPDI-z-n9lA)

In Vitro Enzyme Inhibition Experiment

Inhibition was detected.  Cutoff used —

Table 1 lists the oral and inhalational doses and estimated maximum plasma concentrations of CBD, THC, and THC metabolites used for predicting the magnitude of pharmacokinetic cannabinoid-drug interactions. 

omeprazole

delta-9-tetrahydrocannabinol

5-hydroxyomeprazole

  • CYP2C19 4311137

Cell fraction Pooled human liver microsomes -7999662

Results

Sample Compound measured Value Measurement Study sequence Additional information N replicates

Experimental Conditions

0.1 mg/ml

Commercially available

10 µM

10 . 11-OH-THC Inhibition on CYP3A (id=NPDI-fM7Sfg)

In Vitro Enzyme Inhibition Experiment

Inhibition was detected.  Cutoff used —

Table 1 lists the oral and inhalational doses and estimated maximum plasma concentrations of CBD, THC, and THC metabolites used for predicting the magnitude of pharmacokinetic cannabinoid-drug interactions. 

testosterone

11-hydroxy-delta-9-tetrahydrocannabinol

6beta-hydroxytestosterone

  • CYP3A

Cell fraction Pooled human liver microsomes -7999662

Results

IC50 > 50

Sample Compound measured Value Measurement Study sequence Additional information N replicates

Experimental Conditions

0.1 mg/ml

Commercially available

10 µM

11 . CBD Inhibition on CYP3A (id=NPDI-hthN8w)

In Vitro Enzyme Inhibition Experiment

Inhibition was detected.  Cutoff used —

CBD was predicted to precipitate strong drug interactions (AUCR greater than or equal to 5) mediated by CYP2C9, 2C19, and 3A and moderate drug interactions (AUCR between 1.2 and 5) mediated by CYP1A2 and 2D6 based on the AUCR cutoffs recommended by the FDA (https://www.fda.gov/media/134582/ download). 

Table 1 lists the oral and inhalational doses and estimated maximum plasma concentrations of CBD, THC, and THC metabolites used for predicting the magnitude of pharmacokinetic cannabinoid-drug interactions. 

testosterone

cannabidiol

6beta-hydroxytestosterone

  • CYP3A

Cell fraction Pooled human liver microsomes -7999662

Results

Sample Compound measured Value Measurement Study sequence Additional information N replicates

Experimental Conditions

0.1 mg/ml

Commercially available

10 µM

12 . THC Inhibition on CYP3A (id=NPDI-Rm0CoQ)

In Vitro Enzyme Inhibition Experiment

Inhibition was detected.  Cutoff used —

Table 1 lists the oral and inhalational doses and estimated maximum plasma concentrations of CBD, THC, and THC metabolites used for predicting the magnitude of pharmacokinetic cannabinoid-drug interactions. 

testosterone

delta-9-tetrahydrocannabinol

6beta-hydroxytestosterone

  • CYP3A

Cell fraction Pooled human liver microsomes -7999662

Results

Sample Compound measured Value Measurement Study sequence Additional information N replicates

Experimental Conditions

0.1 mg/ml

Commercially available

10 µM

13 . 11-OH-THC Inhibition of CYP1A2 (id=NPDI-KKxwkg)

In Vitro Enzyme Inhibition Experiment

Inhibition was detected.  Cutoff used —

Table 1 lists the oral and inhalational doses and estimated maximum plasma concentrations of CBD, THC, and THC metabolites used for predicting the magnitude of pharmacokinetic cannabinoid-drug interactions. 

theophylline 1237049

11-hydroxy-delta-9-tetrahydrocannabinol

caffeine 1134439

  • CYP1A2 4312402

Cell fraction Pooled human liver microsomes -7999662

Results

Sample Compound measured Value Measurement Study sequence Additional information N replicates

Experimental Conditions

0.1 mg/ml

Commercially available

50 µM

14 . CBD Inhibition on CYP1A2 (id=NPDI--MuxkQ)

In Vitro Enzyme Inhibition Experiment

Inhibition was detected.  Cutoff used —

CBD was predicted to precipitate strong drug interactions (AUCR greater than or equal to 5) mediated by CYP2C9, 2C19, and 3A and moderate drug interactions (AUCR between 1.2 and 5) mediated by CYP1A2 and 2D6 based on the AUCR cutoffs recommended by the FDA (https://www.fda.gov/media/134582/ download). 

Table 1 lists the oral and inhalational doses and estimated maximum plasma concentrations of CBD, THC, and THC metabolites used for predicting the magnitude of pharmacokinetic cannabinoid-drug interactions. 

theophylline 1237049

cannabidiol

caffeine 1134439

  • CYP1A2 4312402

Cell fraction Pooled human liver microsomes -7999662

Results

Sample Compound measured Value Measurement Study sequence Additional information N replicates

Experimental Conditions

0.1 mg/ml

Commercially available

50 µM

15 . THC Inhibition of CYP1A2 (id=NPDI-5GJkjQ)

In Vitro Enzyme Inhibition Experiment

Inhibition was detected.  Cutoff used —

Table 1 lists the oral and inhalational doses and estimated maximum plasma concentrations of CBD, THC, and THC metabolites used for predicting the magnitude of pharmacokinetic cannabinoid-drug interactions. 

theophylline 1237049

delta-9-tetrahydrocannabinol

caffeine 1134439

  • CYP1A2 4312402

Cell fraction Pooled human liver microsomes -7999662

Results

Sample Compound measured Value Measurement Study sequence Additional information N replicates

Experimental Conditions

0.1 mg/ml

Commercially available

50 µM