TABLE 3

DDI index values estimated from the kinetics of OCT1- and OCT2-mediated PAS uptake inhibition by the inhibitor drugs in vitroa

Inhibitor drugOCT1OCT2
IC50 (μM)DDI indexIC50 (μM)DDI index
[I] = [I]max[I] = [I]max,u[I] = [I]max[I] = [I]max,u
Verapamil1.2 ± 0.350.28 ± 0.012.85 ± 0.1*21.4 ± 5.20.015 ± 0.0010.002 ± 0.001
Cimetidine107.5 ± 19.589.0 ± 17.571.2 ± 14*111.5 ± 1785.2 ± 13.168.2 ± 10.5*
Metformin179.1 ± 330.06 ± 0.010.06 ± 0.01125.6 ± 180.08 ± 0.010.08 ± 0.013
Quinidine4.84 ± 1.42.97 ± 0.821.48 ± 0.41*10.7 ± 1.731.29 ± 0.200.65 ± 0.10*
Omeprazole17.1 ± 2.250.18 ± 0.020.005 ± 0.0015.53 ± 1.310.58 ± 0.160.02 ± 0.001
Lansoprazole25.2 ± 3.70.21 ± 0.020.005 ± 0.00113.0 ± 3.510.41 ± 0.100.01 ± 0.003
  • a The DDI index values were determined using the inhibition constant (IC50) with the maximum concentration in plasma (Cmax; bound plus unbound) ([I]max) and the maximum unbound concentration ([I]max,u) of the anti-TB drugs following the regulatory guidelines described in the text. DDI index values represent means ± SDs obtained from the inhibition constants from three or more independent experiments. *, the result is significant according to FDA guidance for prototypical substrates, in which the DDI index values are greater than the corresponding cutoff values recommended by the regulatory authorities for an [I]max,u value of ≥0.1. The cutoff value is expressed as the value according to the upper limit of the equivalence range suggested by FDA.