TABLE 4

Summary of input parameters and prediction of drug-drug interactions by static model

R value was determined using R = (1+[I]/K_i) and R = [1 + (k_inact × [I])/{(K_I + [I]) × K_deg}] for reversible inhibition and mechanism-based inhibition, respectively. [I] represents [I_u,max] for the inhibition of CYP2C8, and [I_u,in,max] for the inhibition of OATP1B1 of parent drug. In the case of metabolites, [I_u,max] was used as [I] regardless inhibition pathway. K_i values were the geometric mean of all in vitro K_i (or IC₅₀) values that were derived from the University of Washington’s Metabolism and Transport Drug Interaction Database (DIDB) (http://www.druginteractioninfo.org) for each inhibitor against the specific enzyme/transporter in various experimental conditions. The figures in parentheses represent minimum value and maximum value of all reported data, and n is the number of reports.

Inhibitors	Dose (mg)	k_a (/hours)	f_u	I_u,max (μM)	I_u,in,max (μM)	OATP1B1			CYP2C8			CYP3A4
Inhibitors	Dose (mg)	k_a (/hours)	f_u	I_u,max (μM)	I_u,in,max (μM)	K_i or IC₅₀ (μM)	n	R	K_i or IC₅₀ (μM)	n	R	K_i or IC₅₀ (μM)	n	R
Rifampicin	600	0.52^a	0.11^b	3.28^a	3.75^a	1.39 (0.30–50)	47	3.70	30.2	1	1.11	N.A. (18.5, > 240)	3	<1.18
Trimethoprim	200	0.49^a	0.50^c	5.50^a	7.37^a	>100	1	<1.07	27.3 (7.6–122)	11	1.20	>600	3	<1.01
Clopidogrel	300	1.22^a	0.02^d	0.0002^a	0.25^a	3.95	1	1.06	12.3 (3.4–53.6)	3	<1.01	K_I, 87 μM k_inact, 3.18 1/h	1	<1.01
2-oxo clopidogrel	N.A.	N.A.	0.02^d	0.0003	N.A.	8.18	1	<1.00	11.6 (4.2, 32)	2	<1.01	6.37 (3.1, 13.1)	2	<1.01
Clopidogrel carboxylic acid	N.A.	N.A.	0.06^d	2.03	N.A.	>100	1	<1.02	233 (136, 400)	2	<1.01	N.A. (356, > 400)	2	<1.01
Clopidogrel acyl-β-glucuronide	N.A.	N.A.	0.1^d	1.21	N.A.	10.9	1	1.11	K_I, 9.9 μM k_inact, 2.82 1/h	1	10.3	N.A. (27, > 340)	2	<1.05
Gemfibrozil	600	3.50^e	0.0065^f	0.69^e	1.30^e	32.2 (4.0–252)	32	1.04	45.6 (9.3–120)	21	1.02	260 (174–406)	4	<1.01
Gemfibrozil 1-O-β-glucuronide	N.A.	N.A.	0.115^f	5.55^e	N.A.	14.2 (7.9–24)	4	1.39	K_I, 26.7 μM (10–52) k_inact, 4.05 1/h (1.3–13)	9	22.1	267	1	1.02

N.A., not applicable.
↵^a Data from the present cassette small-dose study.
↵^b Boman and Ringberger (1974)
↵^c Wijkström and Westerlund (1983)
↵^d Tornio et al. (2014)
↵^e Honkalammi et al. (2011a)
↵^f Shitara et al. (2004)