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

R value was determined using R = (1+[I]/Ki) and R = [1 + (kinact × [I])/{(KI + [I]) × Kdeg}] for reversible inhibition and mechanism-based inhibition, respectively. [I] represents [Iu,max] for the inhibition of CYP2C8, and [Iu,in,max] for the inhibition of OATP1B1 of parent drug. In the case of metabolites, [Iu,max] was used as [I] regardless inhibition pathway. Ki values were the geometric mean of all in vitro Ki (or IC50) values that were derived from the University of Washington’s Metabolism and Transport Drug Interaction Database (DIDB) ( 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.

InhibitorsDose (mg)ka (/hours)fuIu,max (μM)Iu,in,max (μM)OATP1B1CYP2C8CYP3A4
Ki or IC50 (μM)nRKi or IC50 (μM)nRKi or IC50 (μM)nR
Rifampicin6000.52a0.11b3.28a3.75a1.39 (0.30–50)473.7030.211.11N.A. (18.5, > 240)3<1.18
Trimethoprim2000.49a0.50c5.50a7.37a>1001<1.0727.3 (7.6–122)111.20>6003<1.01
Clopidogrel3001.22a0.02d0.0002a0.25a3.9511.0612.3 (3.4–53.6)3<1.01KI, 87 μM kinact, 3.18 1/h1<1.01
2-oxo clopidogrelN.A.N.A.0.02d0.0003N.A.8.181<1.0011.6 (4.2, 32)2<1.016.37 (3.1, 13.1)2<1.01
Clopidogrel carboxylic acidN.A.N.A.0.06d2.03N.A.>1001<1.02233 (136, 400)2<1.01N.A. (356, > 400)2<1.01
Clopidogrel acyl-β-glucuronideN.A.N.A.0.1d1.21N.A.10.911.11KI, 9.9 μM kinact, 2.82 1/h110.3N.A. (27, > 340)2<1.05
Gemfibrozil6003.50e0.0065f0.69e1.30e32.2 (4.0–252)321.0445.6 (9.3–120)211.02260 (174–406)4<1.01
Gemfibrozil 1-O-β-glucuronideN.A.N.A.0.115f5.55eN.A.14.2 (7.9–24)41.39KI, 26.7 μM (10–52) kinact, 4.05 1/h (1.3–13)922.126711.02
  • 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)