Table 2.

Predicting potential of CYP-based drug-drug interaction.

Inhibitor	Pathway	Dissociation Constant (Ki, μM)	Fraction of Unbound (fu,inc)	Unbound Dissociation Constant (Ki,u, μM)	Peak Plasma Concentration (Cmax, ng/ml)	Inhibitor Concentration ([I], μM)	Predicted R-Values
Simvastatin	CYP3A4	0.51	0.93	0.47	-	0.764	2.61
Promethazine	CYP2D6	0.25	0.88	0.22	19.3 (36)	0.068	1.31*
Tegaserod	CYP3A4	5	0.92	4.61	-	0.796	1.17
Ropinirole	CYP2D6	0.85	0.84	0.71	26.9 (37)	0.103	1.15*
Loratadine	CYP2D6	0.5	0.93	0.47	4.12 (38)	0.011	1.02
Tegaserod	CYP2D6	0.51	0.92	0.47	2.7 (39)	0.009	1.02
Loratadine	CYP2B6	2	0.93	1.86	4.12 (38)	0.011	1.01
Simvastatin	CYP2C9	18.3	0.93	17.03	25.4 (40)	0.061	1.00
Loratadine	CYP2C9	7.6	0.93	7.07	4.12 (38)	0.011	1.00
Tegaserod	CYP2C19	9.2	0.92	8.48	2.7 (39)	0.009	1.00
Tegaserod	CYP2C9	11.4	0.92	10.51	2.7 (39)	0.009	1.00

K_i is the dissociation constant determined in vitro; f_u,inc is the fraction of unbound drug in the incubation mixture and was predicted using the Hallifax-Houston model (41); K_i,u is the unbound dissociation constant estimated as K_i * f_u,inc; C_max is the peak total plasma concentration at the highest clinical dose; [I] is the inhibitor concentration used to predict R values and is equal to C_max, except for CYP3A4 inhibitors administered orally. For simvastatin and tegaserod with CYP3A4, [I] is the estimated gut concentration at the highest proposed clinical dose, 80 mg (191 μM) and 6 mg (19.9 μM), respectively, divided by 250 mL (approximate gut volume); R values were estimated as 1 + [I]/K_i,inc;

^*denotes R values ≥ 1.1 (or ≥ 11 for simvastatin and tegaserod with CYP3A4), indicating a probable clinical CYP450-based DDI.