TABLE 6

In vitro evaluation of inhibition of human renal transporters by verinurad and metabolites M1 and M8

TransporterIC50 (μM)Iu,max/Kia
OCT2
 VerinuradNI
 M1NI
 M8NI
OAT1
 Verinurad14.20.00048
 M1>100
(47.1% inhibition at 100 μM)
<0.00033b
 M8>100
(31.7% inhibition at 100 μM)
<0.00139b
 Verinurad + M1 + M8c<0.00219
OAT3
 Verinurad>100
(19.3% inhibition at 100 μM)
<0.000068b
 M111.90.00559
 M830.40.00914
 Verinurad + M1 + M8c<0.0148
MATE1
 M1>100
(27.5% inhibition at 100 μM)
<0.00033b
 M8NI
MATE2-K
 M1>100
(48.8% inhibition at 100 μM)a
<0.00033a
 M8NI
  • Iu,max, maximum free plasma concentration; Ki, inhibitory constant; Km, Michaelis-Menten constant; NI, no inhibition.

  • a In inhibition studies, probe substrate concentration was sufficiently lower than its Km such that IC50 approximates to Ki.

  • b Risk margin estimate based on highest drug concentration in the assay (which yielded < 50% inhibition).

  • c The combined inhibitory potential of verinurad and its metabolites was calculated as a sum of the individual ratios of exposure in relation to in vitro inhibition constants.