TABLE 3.
Predicted magnitude of pharmacokinetic interactions between CBD or THC interaction and drugs extensively metabolized by P450 enzymes using different static models
| Precipitant | P450Enzyme | Object Drug | Predicted AUCR after Oral Administration of the Precipitant (Inhibition of Hepatic and Gut Metabolism) | Predicted AUCR after Inhalation of the Precipitant (Inhibition of Hepatic Metabolism) | ||||
|---|---|---|---|---|---|---|---|---|
| Model | Model | |||||||
| Aa | Bb | Cc | Dd | Be | C or Df | |||
| CBD (70 mg, Oral) | 1A2 | Theophylline | 3.9 | 3.2 | 2.7 | 2.7 | — | — |
| 2B6 | Ticlopidine | 1.2 | 1.0 | 1.0 | 1.0 | — | — | |
| 2C8 | Repaglinide | 1.1 | 1.0 | 1.0 | 1.0 | — | — | |
| 2C9 | Diclofenac | 2.4 | 1.6 | 1.6 | 1.1 | — | — | |
| 2C19 | Omeprazole | 5.3 | 1.9 | 1.5 | 1.5 | — | — | |
| 2D6 | Dextromethorphan | 1.1 | 1.0 | 1.0 | 1.0 | — | — | |
| 3A | Midazolam | 12.3 | 5.1 | 3.5 | 3.2 | — | — | |
| CBD (700 mg, Oral) | 1A2 | Theophylline | 4.0 | 3.9 | 3.8 | 3.8 | — | — |
| 2B6 | Ticlopidine | 2.2 | 1.2 | 1.1 | 1.1 | — | — | |
| 2C8 | Repaglinide | 1.6 | 1.1 | 1.0 | 1.0 | — | — | |
| 2C9 | Diclofenac | 9.6 | 2.3 | 1.9 | 1.6 | — | — | |
| 2C19 | Omeprazole | 7.3 | 5.1 | 3.9 | 3.9 | — | — | |
| 2D6 | Dextromethorphan | 2.1 | 1.1 | 1.0 | 1.0 | — | — | |
| 3A | Midazolam | 14.8 | 12.0 | 9.8 | 9.7 | — | — | |
| CBD (2000 mg, Oral) | 1A2 | Theophylline | 4.0 | 3.9 | 3.9 | 3.9 | — | — |
| 2B6 | Ticlopidine | 3.1 | 1.4 | 1.2 | 1.2 | — | — | |
| 2C8 | Repaglinide | 2.2 | 1.2 | 1.1 | 1.1 | — | — | |
| 2C9 | Diclofenac | 20.7 | 3.8 | 2.6 | 2.4 | — | — | |
| 2C19 | Omeprazole | 7.6 | 6.5 | 5.6 | 5.6 | — | — | |
| 2D6 | Dextromethorphan | 4.1 | 1.3 | 1.1 | 1.1 | — | — | |
| 3A | Midazolam | 15.0 | 13.9 | 12.6 | 12.6 | — | — | |
| THC (20 mg, Oral) | 1A2 | Theophylline | 1.1 | 1.0 | 1.0 | 1.0 | — | — |
| 2B6 | Ticlopidine | 1.0 | 1.0 | 1.0 | 1.0 | — | — | |
| 2C8 | Repaglinide | 1.0 | 1.0 | 1.0 | 1.0 | — | — | |
| 2C9 | Diclofenac | 2.1 | 1.6 | 1.6 | 1.1 | — | — | |
| 2C19 | Omeprazole | 1.0 | 1.0 | 1.0 | 1.0 | — | — | |
| 2D6 | Dextromethorphan | 1.0 | 1.0 | 1.0 | 1.0 | — | — | |
| 3A | Midazolam | 1.8 | 1.8 | 1.8 | 1.0 | — | — | |
| THC (130 mg, Oral) | 1A2 | Theophylline | 1.4 | 1.0 | 1.0 | 1.0 | — | — |
| 2B6 | Ticlopidine | 1.0 | 1.0 | 1.0 | 1.0 | — | — | |
| 2C8 | Repaglinide | 1.0 | 1.0 | 1.0 | 1.0 | — | — | |
| 2C9 | Diclofenac | 6.6 | 2.1 | 1.7 | 1.4 | — | — | |
| 2C19 | Omeprazole | 1.0 | 1.0 | 1.0 | 1.0 | — | — | |
| 2D6 | Dextromethorphan | 1.0 | 1.0 | 1.0 | 1.0 | — | — | |
| 3A | Midazolam | 1.8 | 1.8 | 1.8 | 1.0 | — | — | |
| THC (160 mg, Oral) | 1A2 | Theophylline | 1.5 | 1.1 | 1.0 | 1.0 | — | — |
| 2B6 | Ticlopidine | 1.0 | 1.0 | 1.0 | 1.0 | — | — | |
| 2C8 | Repaglinide | 1.0 | 1.0 | 1.0 | 1.0 | — | — | |
| 2C9 | Diclofenac | 7.6 | 2.3 | 1.7 | 1.4 | — | — | |
| 2C19 | Omeprazole | 1.0 | 1.0 | 1.0 | 1.0 | — | — | |
| 2D6 | Dextromethorphan | 1.1 | 1.0 | 1.0 | 1.0 | — | — | |
| 3A | Midazolam | 1.8 | 1.8 | 1.8 | 1.0 | — | — | |
| THC (20 mg, Inhaled) | 1A2 | Theophylline | — | — | — | — | 1.1 | 1.0 |
| 2B6 | Ticlopidine | — | — | — | — | 1.0 | 1.0 | |
| 2C8 | Repaglinide | — | — | — | — | 1.0 | 1.0 | |
| 2C9 | Diclofenac | — | — | — | — | 1.5 | 1.1 | |
| 2C19 | Omeprazole | — | — | — | — | 1.0 | 1.0 | |
| 2D6 | Dextromethorphan | — | — | — | — | 1.0 | 1.0 | |
| 3A | Midazolam | — | — | — | — | 1.0 | 1.0 | |
| THC (75 mg, Inhaled) | 1A2 | Theophylline | — | — | — | — | 1.2 | 1.0 |
| 2B6 | Ticlopidine | — | — | — | — | 1.0 | 1.0 | |
| 2C8 | Repaglinide | — | — | — | — | 1.0 | 1.0 | |
| 2C9 | Diclofenac | — | — | — | — | 2.3 | 1.2 | |
| 2C19 | Omeprazole | — | — | — | — | 1.0 | 1.0 | |
| 2D6 | Dextromethorphan | — | — | — | — | 1.0 | 1.0 | |
| 3A | Midazolam | — | — | — | — | 1.0 | 1.0 | |
| THC (100 mg, Inhaled) | 1A2 | Theophylline | — | — | — | — | 1.2 | 1.0 |
| 2B6 | Ticlopidine | — | — | — | — | 1.0 | 1.0 | |
| 2C8 | Repaglinide | — | — | — | — | 1.0 | 1.0 | |
| 2C9 | Diclofenac | — | — | — | — | 2.9 | 1.4 | |
| 2C19 | Omeprazole | — | — | — | — | 1.0 | 1.0 | |
| 2D6 | Dextromethorphan | — | — | — | — | 1.0 | 1.0 | |
| 3A | Midazolam | — | — | — | — | 1.0 | 1.0 | |
kapredicted AUCR using [I]H = Cmax,hepatic inlet,u in eq. 5 and 6 and [I]G = calculated maximum intestinal fluid solubility in eq. 7 and 8
bpredicted AUCR using [I]H = Cmax,sys,u in eq. 5 and 6 and [I]G = calculated maximum intestinal fluid solubility in eq. 7 and 8
cpredicted AUCR using [I]H = Cave,sys,u in eq. 5 and 6 and [I]G = calculated maximum intestinal fluid solubility in eq. 7 and 8
epredicted AUCR using only [I]H = Cmax,sys,u in eq. 6
fpredicted AUCR using only [I]H = Cave,sys,u in eq. 6
Dashes (—) in cells indicate not relevant.
Bold values represent AUCR > 1.25 (cutoff recommended by US Food and Drug Administration).
Cmax,hepatic inlet,u and Cave,portal,u of CBD and THC and Cmax,sys,u and Cave,sys,u of CBD, THC, and their metabolites are provided in Supplemental Table 2. Maximum intestinal fluid solubility of CBD and THC is from Bansal et al. (2020).