TABLE 2

DDI index values estimated from the kinetics of OAT1- and OAT3-mediated PAS uptake inhibition by NSAIDs and PPIs in vitroa

Inhibitor drugOAT1OAT3
IC50 (μM)DDI indexIC50 (μM)DDI index
[I] = [I]max[I] = [I]max,u[I] = [I]max[I] = [I]max,u
Probenecid16.3 ± 3.614.9 ± 2.42.23 ± 0.96*24.6 ± 4.29.91 ± 1.211.48 ± 0.26*
Indomethacin1.91 ± 0.202.13 ± 0.20.02 ± 0.0012.18 ± 0.251.87 ± 0.220.02 ± 0.002
Ibuprofen5.1 ± 0.7853.0 ± 8.90.53 ± 0.09*1.98 ± 0.24135.6 ± 181.35 ± 0.18*
Diclofenac1.8 ± 0.125.4 ± 0.330.02 ± 0.0012.0 ± 0.354.65 ± 0.820.02 ± 0.003
Naproxen4.13 ± 0.2565.4 ± 4.00.65 ± 0.04*4.6 ± 0.2358.4 ± 2.910.60 ± 0.02*
Omeprazole1.76 ± 0.111.75 ± 0.110.05 ± 0.0035.1 ± 0.780.62 ± 0.100.02 ± 0.003
Lansoprazole4.13 ± 0.261.18 ± 0.070.03 ± 0.0022.18 ± 0.252.25 ± 0.270.07 ± 0.002
  • a The DDI index values were determined using the inhibition constant (IC50) with the maximum concentration in plasma (Cmax; bound plus unbound drug) ([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.