Cannabis L. (Cannabis sativa)
Cannabidiol Is a Potent Inhibitor of the Catalytic Activity of Cytochrome P450 2C19 CSV JSON

The present study investigated the inhibitory effect of cannabidiol (CBD), a major constituent of marijuana, on the catalytic activity of cytochrome P450 2C19 (CYP2C19). (S)-Mephenytoin 4'-hydroxylase activities of human liver microsomes (HLMs) and recombinant CYP2C19 were inhibited by CBD in a concentration-dependent manner (IC₅₀ = 8.70 and 2.51 µM, respectively). Omeprazole 5-hydroxylase and 3-O-methylfluorescein O-demethylase activities in recombinant CYP2C19 were also strongly inhibited by CBD (IC₅₀ = 1.55 and 1.79 µM, respectively). Kinetic analysis for inhibition revealed that CBD showed a mixed-type inhibition against (S)-mephenytoin 4'-hydroxylation by recombinant CYP2C19. To clarify the structural requirements for CBD-mediated CYP2C19 inhibition, the effects of CBD-related compounds on CYP2C19 activity were examined. Olivetol inhibited the (S)-mephenytoin 4'-hydroxylase activity of recombinant CYP2C19 with the IC₅₀ value of 15.3 µM, whereas d-limonene slightly inhibited the activity (IC₅₀ > 50 µM). The inhibitory effect of CBD-2'-monomethyl ether (IC₅₀ = 1.88 µM) on CYP2C19 was comparable to that of CBD, although the inhibitory potency of CBD-2',6'-dimethyl ether (IC₅₀ = 14.8 µM) was lower than that of CBD. Cannabidivarin, possessing a propyl side chain, showed slightly less potent inhibition (IC₅₀ = 3.45 µM) as compared with CBD, whereas orcinol and resorcinol did not inhibit CYP2C19 activity at all. These results indicate that CBD caused potent CYP2C19 inhibition, in which one free phenolic hydroxyl group and the pentyl side chain of CBD may play important roles.

1 . 2H-CBD-OMF (id=NPDI-E2Dy1A)

In Vitro Enzyme Inhibition Experiment

Inhibition was detected.  Cutoff used — Not specified

3-O-Methylfluorescein

fluorescein

  • CYP2C19 4311137

Recombinant expression system Baculovirus-insect cells
Cytochrome B5 Not available

Results

Table 2

Compound measured Measurement Value Study sequence Additional information N replicates

Experimental Conditions

Commercially available

200 μL

30 min

NADPH regenerating system

10 min

No NADPH with precipitant

2 . CBD-OMF (id=NPDI-F2AXtQ)

In Vitro Enzyme Inhibition Experiment

Inhibition was detected.  Cutoff used — Not specified

3-O-Methylfluorescein

cannabidiol (CBD)

fluorescein

  • CYP2C19 4311137

Recombinant expression system Baculovirus-insect cells
Cytochrome B5 Not available

Results

Table 2

Compound measured Measurement Value Study sequence Additional information N replicates

Experimental Conditions

Commercially available

200 μL

30 min

NADPH regenerating system

10 min

No NADPH with precipitant

3 . CBDM-OMF (id=NPDI-PMEwbg)

In Vitro Enzyme Inhibition Experiment

Inhibition was detected.  Cutoff used — Not specified

3-O-Methylfluorescein

fluorescein

  • CYP2C19 4311137

Recombinant expression system Baculovirus-insect cells
Cytochrome B5 Not available

Results

Table 2

Compound measured Measurement Value Study sequence Additional information N replicates

Experimental Conditions

Commercially available

200 μL

30 min

NADPH regenerating system

10 min

No NADPH with precipitant

4 . CBDD-OMF (id=NPDI-A4_kwg)

In Vitro Enzyme Inhibition Experiment

Inhibition was detected.  Cutoff used — Not specified

3-O-Methylfluorescein

fluorescein

  • CYP2C19 4311137

Recombinant expression system Baculovirus-insect cells
Cytochrome B5 Not available

Results

Table 2

Compound measured Measurement Value Study sequence Additional information N replicates

Experimental Conditions

Commercially available

200 μL

30 min

NADPH regenerating system

10 min

No NADPH with precipitant

5 . CBDV-OMF (id=NPDI-wcUiKQ)

In Vitro Enzyme Inhibition Experiment

Inhibition was detected.  Cutoff used — Not specified

3-O-Methylfluorescein

cannabidivarin

fluorescein

  • CYP2C19 4311137

Recombinant expression system Baculovirus-insect cells
Cytochrome B5 Not available

Results

Table 2

Compound measured Measurement Value Study sequence Additional information N replicates

Experimental Conditions

Commercially available

200 μL

30 min

NADPH regenerating system

10 min

No NADPH with precipitant

6 . THC-OMF (id=NPDI-_k7VAQ)

In Vitro Enzyme Inhibition Experiment

Inhibition was detected.  Cutoff used — Not specified

3-O-Methylfluorescein

fluorescein

  • CYP2C19 4311137

Recombinant expression system Baculovirus-insect cells
Cytochrome B5 Not available

Results

Table 2

Compound measured Measurement Value Study sequence Additional information N replicates

Experimental Conditions

Commercially available

200 μL

30 min

NADPH regenerating system

10 min

No NADPH with precipitant

7 . 2H-CBD-(S)-Mephenytoin (id=NPDI-egkFFQ)

In Vitro Enzyme Inhibition Experiment

Inhibition was detected.  Cutoff used — Not specified

mephenytoin, (S)-

4-hydroxymephenytoin, (S)-

  • CYP2C19 4311137

Recombinant expression system Baculovirus-insect cells
Cytochrome B5 Not available

Results

%inhibition at 6 μM (Fig 2F)
IC50 (Table 2)
Ki (Table 3)

Compound measured Measurement Value Study sequence Additional information N replicates

Experimental Conditions

Commercially available

250 μL

40 min

NADPH regenerating system

5 min

No NADPH with precipitant

8 . CBD-(S)-Mephenytoin (id=NPDI-es-pWA)

In Vitro Enzyme Inhibition Experiment

Inhibition was detected.  Cutoff used — Not specified

mephenytoin, (S)-

cannabidiol (CBD)

4-hydroxymephenytoin, (S)-

  • CYP2C19 4311137

Recombinant expression system Baculovirus-insect cells
Cytochrome B5 Not available

Results

%inhibition at 10 μM of CBD (Fig. 1)
IC50 (Table 1), Ki (Table 3)

Compound measured Measurement Value Study sequence Additional information N replicates

Experimental Conditions

Commercially available

250 μL

40 min

NADPH regenerating system

5 min

No NADPH with precipitant

9 . CBDM-(S)-Mephenytoin (id=NPDI-w7jBLw)

In Vitro Enzyme Inhibition Experiment

Inhibition was detected.  Cutoff used — Not specified

mephenytoin, (S)-

4-hydroxymephenytoin, (S)-

  • CYP2C19 4311137

Recombinant expression system Baculovirus-insect cells
Cytochrome B5 Not available

Results

%inhibition at 10 μM (Fig.2C)
IC50 (Table 2)
Ki (Table 3)

Compound measured Measurement Value Study sequence Additional information N replicates

Experimental Conditions

Commercially available

250 μL

40 min

NADPH regenerating system

5 min

No NADPH with precipitant

10 . CBDD-(S)-mephenytoin (id=NPDI-8HM-ew)

In Vitro Enzyme Inhibition Experiment

Inhibition was detected.  Cutoff used — Not specified

mephenytoin, (S)-

4-hydroxymephenytoin, (S)-

  • CYP2C19 4311137

Recombinant expression system Baculovirus-insect cells
Cytochrome B5 Not available

Results

%inhibition at 50 μM (Fig 2C).
IC50 (Table 2).
Ki (Table 3).

Compound measured Measurement Value Study sequence Additional information N replicates

Experimental Conditions

Commercially available

250 μL

40 min

NADPH regenerating system

5 min

No NADPH with precipitant

11 . CBDV-(S)-Mephenytoin (id=NPDI-k7I3rg)

In Vitro Enzyme Inhibition Experiment

Inhibition was detected.  Cutoff used — Not specified

mephenytoin, (S)-

cannabidivarin

4-hydroxymephenytoin, (S)-

  • CYP2C19 4311137

Recombinant expression system Baculovirus-insect cells
Cytochrome B5 Not available

Results

%inhibition at 10 μM (Fig 2E)
IC50 (Table 2)
Ki (Table 3)

Compound measured Measurement Value Study sequence Additional information N replicates

Experimental Conditions

Commercially available

250 μL

40 min

NADPH regenerating system

5 min

No NADPH with precipitant

12 . THC-(S)-Mephenytoin (id=NPDI-FGSLRQ)

In Vitro Enzyme Inhibition Experiment

Inhibition was detected.  Cutoff used — Not specified

mephenytoin, (S)-

4-hydroxymephenytoin, (S)-

  • CYP2C19 4311137

Recombinant expression system Baculovirus-insect cells
Cytochrome B5 Not available

Results

% inhibition at 10 μM estimated from Fig 2D.
IC50 (Table 2).
Ki (Table 3)

Compound measured Measurement Value Study sequence Additional information N replicates

Experimental Conditions

Commercially available

250 μL

40 min

NADPH regenerating system

5 min

No NADPH with precipitant

13 . 2H-CBD-omeprazole (id=NPDI-3Crf-w)

In Vitro Enzyme Inhibition Experiment

Inhibition was detected.  Cutoff used — Not specified

omeprazole

5-hydroxyomeprazole

  • CYP2C19 4311137

Recombinant expression system Baculovirus-insect cells
Cytochrome B5 Not available

Results

Table 2

Compound measured Measurement Value Study sequence Additional information N replicates

Experimental Conditions

Commercially available

250 μL

40 min

NADPH regenerating system

5 min

No NADPH with precipitant

14 . CBD-omeprazole (id=NPDI-ILAq5w)

In Vitro Enzyme Inhibition Experiment

Inhibition was detected.  Cutoff used — Not specified

omeprazole

cannabidiol (CBD)

5-hydroxyomeprazole

  • CYP2C19 4311137

Recombinant expression system Baculovirus-insect cells
Cytochrome B5 Not available

Results

Table 2

Compound measured Measurement Value Study sequence Additional information N replicates

Experimental Conditions

Commercially available

250 μL

40 min

NADPH regenerating system

5 min

No NADPH with precipitant

15 . CBDM-omeprazole (id=NPDI-QtzrqQ)

In Vitro Enzyme Inhibition Experiment

Inhibition was detected.  Cutoff used — Not specified

omeprazole

5-hydroxyomeprazole

  • CYP2C19 4311137

Recombinant expression system Baculovirus-insect cells
Cytochrome B5 Not available

Results

Table 2

Compound measured Measurement Value Study sequence Additional information N replicates

Experimental Conditions

Commercially available

250 μL

40 min

NADPH regenerating system

5 min

No NADPH with precipitant

16 . CBDD-omeprazole (id=NPDI-L4dcwg)

In Vitro Enzyme Inhibition Experiment

Inhibition was detected.  Cutoff used — Not specified

omeprazole

5-hydroxyomeprazole

  • CYP2C19 4311137

Recombinant expression system Baculovirus-insect cells
Cytochrome B5 Not available

Results

Table 2

Compound measured Measurement Value Study sequence Additional information N replicates

Experimental Conditions

Commercially available

250 μL

40 min

NADPH regenerating system

5 min

No NADPH with precipitant

17 . CBDV-omeprazole (id=NPDI-3EHgSg)

In Vitro Enzyme Inhibition Experiment

Inhibition was detected.  Cutoff used — Not specified

omeprazole

cannabidivarin

5-hydroxyomeprazole

  • CYP2C19 4311137

Recombinant expression system Baculovirus-insect cells
Cytochrome B5 Not available

Results

Table 2

Compound measured Measurement Value Study sequence Additional information N replicates

Experimental Conditions

Commercially available

250 μL

40 min

NADPH regenerating system

5 min

No NADPH with precipitant

18 . THC-omeprazole (id=NPDI-F14zbg)

In Vitro Enzyme Inhibition Experiment

Inhibition was detected.  Cutoff used — Not specified

omeprazole

5-hydroxyomeprazole

  • CYP2C19 4311137

Recombinant expression system Baculovirus-insect cells
Cytochrome B5 Not available

Results

Table 2

Compound measured Measurement Value Study sequence Additional information N replicates

Experimental Conditions

Commercially available

250 μL

40 min

NADPH regenerating system

5 min

No NADPH with precipitant