TABLE 1.

IC₅₀ and % of inhibition of selected CYP450s by Fenfluramine (FFA) and norfenfluramine (nFFA) and the calculated ratio of intrinsic clearance values R₁

CYP	Substrate	IC50 (µM)	Inhibition (%)	Basic model		Static mechanistic model
Enzyme				R1	Potential for clinical inhibition a	AUCR	Potential for clinical inhibition c
FFA
CYP1A2	Phenacetin	>60	NC	NC	No	1.01	No
CYP2B6	Efavirenz	>60	6.1	1.01	No	1.01	No
CYP2C8	Amodiaquine	>60	5.9	1.01	No	1.01	No
CYP2C9	Diclofenac	>60	2.4	1.01	No	1.01	No
CYP2C19	S‐Mephenytoin	>60	14	1.01	No	1.01	No
CYP2D6	Dextromethorphan	4.7 ± 0.2	90	1.07	Yes	1.17	No
CYP3A4	Midazolam	>600	NC	NC R1,gut = 1.78	No No b	1.00	No
CYP3A4	Testosterone	>600	18	1.00 R1,gut = 1.81	No No b	1.00	No
nFFA
CYP1A2	Phenacetin	>100	NC	NC	No	1.00	No
CYP2B6	Efavirenz	>100	23	1.00	No	1.00	No
CYP2C8	Amodiaquine	>100	NC	NC	No	1.00	No
CYP2C9	Diclofenac	>100	NC	NC	No	1.00	No
CYP2C19	S‐Mephenytoin	>100	2.9	1.00	No	1.00	No
CYP2D6	Dextromethorphan	16 ± 1	82	1.01	No	1.01	No
CYP3A4	Midazolam	>100	NC	NC	No	1.00	No
CYP3A4	Testosterone	>100	2.8	1.00	No	1.00	No

NC, not calculated. No value was obtained, as rates of metabolite formation were higher than control rates.

R₁ = 1 + (I_max,u/K_i,u); R_1,gut = 1 + (I_gut/K_i,u) and [I]_gut = dose (µmol)/0.25 L (U.S. FDA, 2020).

AUCR = (1/[A_g × B_g] × (1−F_g) + F_g) × (1/[A_h × B_h] × f_m + (1 − f_m)).

^a Potential to inhibit if R₁ ≥ 1.02.

^b Potential to inhibit if R_1,gut ≥ 11.

^c Potential to inhibit if AUCR ≥ 1.25.