TABLE 4

Dynamic model fit parameters K_i, K_I, and k_inact from IC₅₀-shift experimental design considering kinetics of inhibitor depletion, compared with K_I and k_inact values determined from traditional experimental design and parameter fitting

Values are ± S.E. or a range of values as appropriate.

		IC₅₀ Shift by Substrate Addition (Fit with Dynamic Model)			Traditional Dilution Method (Range of Reference Values)^{^a}
Compound	P450	K_i	K_I	k_inact	K_I	k_inact
		µM	µM	min-1	µM	min-1
Clarithromycin	CYP3A4	62.6 ± 8.5	25.6 ± 12.2	0.0204 ± 0.0059	13.2–41.4	0.0192–0.063
Dasatinib	CYP3A4	5.25 ± 0.71	1.17 ± 0.39	0.0245 ± 0.0044	2.6–6.3	0.024–0.034
Delavirdine	CYP3A4	14.5 ± 2.1	1.45 ± 0.85	0.0716 ± 0.0079	3.8–15.9	0.056–0.29
	CYP2D6	15.9 ± 1.5	3.34 ± 0.97	0.0265 ± 0.0030	3.89 ± 1.07	0.0215 ± 0.0030
Diltiazem	CYP3A4	23.2 ± 5.2	1.76 ± 0.85	0.00779 ± 0.00227	0.48–18.1	0.005–0.019
Erythromycin	CYP3A4	20.7 ± 2.3	5.27 ± 2.19	0.0148 ± 0.0034	1.7–17	0.017–0.081
Mibefradil	CYP3A4	0.297 ± 0.038	0.0200 ± 0.0033	0.0539 ± 0.0045	0.13–2.3	0.042–0.7
	CYP2D6	0.410 ± 0.040	0.161 ± 0.054	0.0164 ± 0.0031	1.09 ± 0.31	0.0220 ± 0.0021
Mifepristone	CYP3A4	3.59 ± 0.67	0.308 ± 0.041	0.0541 ± 0.0040	0.61–1.6	0.061–0.091
	CYP2C9	1.83 ± 0.31	1.86 ± 0.88	0.0307 ± 0.0096	None reported
Nefazodone	CYP3A4	2.82 ± 0.95	0.414 ± 0.190	0.205 ± 0.072	1.0–1.6	0.09–0.094
Nicardipine	CYP3A4	0.338 ± 0.043	0.0424 ± 0.0141	0.0864 ± 0.0175	0.72–1.3	0.047–0.06
Paroxetine	CYP2D6	0.721 ± 0.068	0.0789 ± 0.0141	0.0790 ± 0.0087	0.81–4.85	0.074–0.17
Ritonavir	CYP3A4	0.00456 ± 0.00038	0.0527 ± 0.0239	0.439 ± 0.180	0.0106–0.5	0.05 - 0.45
Saquinavir	CYP3A4	0.251 ± 0.027	0.484 ± 0.167	0.0416 ± 0.0091	1.54–5.9	0.026–0.0379
	CYP2D6	3.41 ± 0.82	2.99 ± 3.24	0.0388 ± 0.0322	None reported
Tienilic acid	CYP2C9	0.690 ± 0.093	0.0969 ± 0.0605	0.0840 ± 0.0161	1.0–4.5	0.066–0.46
Troleandomycin	CYP3A4	2.42 ± 0.14	0.271 ± 0.047	0.0404 ± 0.0025	0.19–2.4	0.032–0.171
Verapamil	CYP3A4	13.0 ± 2.06	0.201 ± 0.058	0.0260 ± 0.0017	0.74–3.5	0.023–0.07

↵^a Reference values compiled from the following sources: Mayhew et al., 2000; Bertelsen et al., 2003; Ito et al., 2003; Zhao et al., 2005, 2007; Obach et al., 2007; Watanabe et al., 2007; Berry and Zhao, 2008; Perloff et al., 2009; Li et al., 2009; Mori et al., 2009; Xu et al., 2009; Kirby et al., 2011; Albaugh et al., 2012; Kenny et al., 2012; Amgen in-house data; University of Washington Drug Interaction Database (www.druginteractioninfo.org).