TABLE 1

CL_int values in human and monkey intestinal microsomes and F_{g, human(observed)} values calculated from pharmacokinetic parameters in humans

CL_int values were determined from metabolic stabilities of 18 CYP3A substrates with pooled MIM and HIM. Linearity of metabolic activity for the microsome concentration (0.001–0.2 mg of protein/ml), the substrate concentration (10–200 nM), and the incubation time (15 or 30 min) was confirmed and CL_int values were determined. Each value represents the mean of duplicate measurements.

Compounds	CL_int		F_{g, human(observed)}	References
Compounds	HIM	MIM	F_{g, human(observed)}	References
	ml/(min · mg protein)
Buspirone	0.130	0.227	0.11^{^a}	Gertz et al., 2008
Carbamazepine	—^{^c}	—	1.00^{^b}	Gérardin et al., 1990
Cisapride	0.088	0.204	0.55^{^a}	Gertz et al., 2008
Cyclosporine	0.063	0.172	0.77^{^a}	Gertz et al., 2008
Diazepam	—	—	1.00^{^b}	Friedman et al., 1992; Greenblatt et al., 1980
Diltiazem	0.024	0.094	0.91^{^a}	Sigusch et al., 1994
Felodipine	0.871	1.462	0.53^{^a}	Gertz et al., 2008
Lovastatin	2.143	3.019	0.065^{^a}	Yang et al., 2007
Midazolam	0.204	0.358	0.56^{^a}	Gertz et al., 2008
Nicardipine	2.035	5.893	0.64^{^a}	Uno et al., 2000
Nifedipine	0.057	0.156	0.62^{^a}	Gertz et al., 2008
Nimodipine	0.519	1.223	0.64^{^a}	Fuhr et al., 1998
Nitrendipine	0.221	0.642	0.44^{^a}	Soons et al., 1991
Quinidine	—	0.135	0.92^{^a}	Gertz et al., 2008
Saquinavir	1.799	5.133	0.54^{^a}	Gertz et al., 2008
Simvastatin	1.859	4.247	0.14^{^a}	Gertz et al., 2008
Triazolam	—	—	0.64^{^a}	Gertz et al., 2008
Verapamil	0.205	0.754	0.71^{^a}	Gertz et al., 2008

↵a F_{g, human} is the intestinal availability estimated from GFJ interaction studies (eq. 11).
↵b It is reported that the bioavailability of carbamazepine and diazepam is 1.
↵c —, when the remaining amount after incubation for 30 min with 0.2 mg of microsomal protein/ml was >90%, CL_int values were not calculated [CL_int <0.018 ml/(min · mg protein)].