TABLE 5

Omeprazole and esomeprazole as CYP2C19 inhibitors

PPI	Substrate	Inhibition Type	Parameter(s)^{^a}			% Inhibition_predicted^{^b}				% Inhibition_{in vivo} (90% CI)^{^c}
PPI	Substrate	Inhibition Type	K_i,u	K_I,u	k_inact	C_max	C_max,u	C_max.portal	C_max,portal,u	% Inhibition_{in vivo} (90% CI)^{^c}
			μM	μM	min⁻¹
Omeprazole	Diazepam	Reversible	4.0			7	<1	30	<1	38 (28, 49)^{^d} 46 (28, 61)^{^e}
	(S)-Mephenytoin		6.3			5	<1	21	1
	CEC		0.6			33	2	74	12
	(S)-Mephenytoin (HLM)		3.3			8	<1	34	3
	Diazepam	Metabolism-Dependent		3.40	0.039	86	26	96	66	38 (28, 49)^{^d} 46 (28, 61)^{^e}
	(S)-Mephenytoin			2.30	0.048	92	38	98	77
	(S)-Mephenytoin (HLM)			0.84	0.030	94	51	98	85
	Diazepam	Metabolism-Dependent + Reversible	4.0	3.40	0.039	87	26	97	66	38 (28, 49)^{^d} 46 (28, 61)^{^e}
	(S)-Mephenytoin		6.3	2.30	0.048	92	38	98	77
	(S)-Mephenytoin (HLM)		3.3	0.84	0.030	95	51	98	85
Esomeprazole	Diazepam	Reversible	2.3			69	6	87	17	79 (52, 99)
	(S)-Mephenytoin		0.6			89	19	96	42
	CEC		0.3			96	42	99	68
	(S)-Mephenytoin (HLM)		1.7			75	8	90	21
	Diazepam	Metabolism-Dependent		1.70	0.076	99	93	99	97	79 (52, 99)
	(S)-Mephenytoin			2.30	0.204	99	96	100	99
	(S)-Mephenytoin (HLM)			0.72	0.049	99	95	99	98
	Diazepam	Metabolism-Dependent + Reversible	2.3	1.70	0.076	100	93	100	98	79 (52, 99)
	(S)-Mephenytoin		0.6	2.30	0.204	100	97	100	99
	(S)-Mephenytoin (HLM)		1.7	0.72	0.049	100	95	100	98

↵a Unless otherwise indicated, the K_i,u is the IC₅₀ obtained with rCYP2C19 (Table 2) divided by 2 (not corrected for f_u,inc since binding to rCYP2C19 was negligible: f_u,inc >0.97). For (S)-mephenytoin with HLM only, the K_i,u is the IC₅₀ obtained with HLM, corrected for f_u,inc and then divided by 2. Because time-dependent shifts in IC₅₀ were noted, the HLM- and rCYP2C19-derived parameters (k_inact and K_I) were used to estimate the contribution of metabolism-dependent inhibition. K_I was also corrected for f_u,inc.
↵b Percentage of inhibition_predicted was determined as described under Materials and Methods. C_max (C_max,u) values for each PPI were based on those reported for a specific diazepam drug interaction; 0.3 (0.02) μM after 20 mg of oral omeprazole, and 5.2 (0.16) μM after 30 mg of oral esomeprazole (see Supplemental Table S2). C_max,portal values were 1.7 μM (omeprazole) and 15.5 μM (esomeprazole). Corresponding C_max,portal,u values were 0.1 μM (omeprazole) and 0.47 μM (esomeprazole).
↵c Percentage of inhibition_{in vivo} was calculated based on the reported effect of each PPI on the AUC of diazepam (see Materials and Methods, eqs. 17 and 18).
↵d Percentage of inhibition_{in vivo} was calculated based on the AUC_i/AUC_c ratio reported by Ishizaki et al. (1995).
↵e Percentage of inhibition_{in vivo} was calculated based on the AUC_i/AUC_c ratio reported by Andersson et al. (1990).