Table 5.

Predicted cytochrome P450-mediated clinical drug interaction potential of THC administered orally or by inhalation.

Enzyme	IC₅₀ or K_i corrected for binding (μM)^b	Oral Dose (40 mg)			Inhaled Dose (34 mg)	Reference
Enzyme	IC₅₀ or K_i corrected for binding (μM)^b	AUCR_gut	AUCR_hep	AUCR_sys	AUCR_sys	Reference
CYP1A1	0.14	N/A	1.15	1.01	1.11	(Yamaori et al, 2010)
CYP1A2^a	0.23	N/A	1.10	1.01	1.07	(Yamaori et al, 2010)
CYP1B1	0.074	N/A	1.30	1.03	1.21	(Yamaori et al, 2010)
CYP2A6	0.87	N/A	1.03	1.00	1.02	(Yamaori et al, 2011)
CYP2B6	0.084	N/A	1.26	1.02	1.18	(Yamaori et al, 2011)
CYP2D6	0.51	N/A	1.04	1.00	1.03	(Yamaori et al, 2011)
CYP2C9^a	0.041	N/A	1.53	1.05	1.37	(Yamaori et al, 2012)
CYP2C19^a	0.057	N/A	1.38	1.03	1.27	(Jiang et al., 2013)
CYP3A4	>1.5	>340	1.01	1.00	1.00-1.01	(Yamaori et al, 2011)
CYP3A5	1.1	480	1.02	1.00	1.01	(Yamaori et al, 2011)

Clinical studies suggest the potential for marijuana-drug interactions.

Published K_i or IC₅₀ values (Table 3) corrected for non-specific binding to assay materials using f_u,p = 0.03 (based on plasma protein binding of THC) as a surrogate (Garrett and Hunt, 1974; Klausneret al., 1975; Widman et al., 1974).

Predicted potential for drug interactions mediated by inhibition of cytochromes P450 by THC consumed orally or inhaled. Predicted AUC ratio (AUCR) for intestine (AUCR_gut) ≥ 11, liver (AUCR_hep) ≥ 1.25, and systemic circulation (AUCR_sys) ≥ 1.02 indicate strong presystemic intestinal, presystemic hepatic, or systemic drug interaction potential, respectively. Values in shaded cells exceed the cut-off values recommended by the FDA (FDA, 2017).

AUCR_gut = 1+(I_g/binding corrected K_i or IC₅₀), where intestinal luminal concentration (I_g) was calculated as dose/250 mL (507,200 nM)
AUCR_hep = 1+(I_hep,u/K_i or IC₅₀), where I_hep,u was calculated as 22 nM $[f_{u, p} \times (C_{\max} + \frac{F_{a} \times k_{a} \times Dose}{{}^{Q_{h e p}}∕_{R_{B}}})]$ , where C_max= 64 nM (Lile et al., 2013); F_a = 1 (estimated based on FDA guidance), k_a = 0.02 min⁻¹ (estimated using Phoenix WinNonlin and confirmed by (Heuberger et al., 2015)), Q_heP (liver blood flow) = 1500 ml/min (assumption), R_B (blood:plasma ratio) = 0.4 (Schwilke et al., 2009)
AUCR_sys = 1+(I_sys/K_i or IC₅₀), where I_sys = C_max,u = 1.91 nM (orally) (Lile et al., 2013) or 15.5 nM (inhalation) (Huestis et al., 1992)