Abstract
Verinurad (RDEA3170) lowers serum uric acid by inhibiting URAT1, a urate/carboxylate co‐transporter in the proximal tubule (PT) of the kidney. In a recent clinical trial, verinurad also reduced proteinuria, but the mechanism remains unknown. One proposed hypothesis is that the inhibition of URAT1 augments protein reabsorption by increasing intracellular lactate in proximal tubule cells. The increased availability of lactate may lead to a restoration of the reabsorption of protein by increasing ATP levels and/ or improving endocytosis of protein by lowering endosomal pH. The goal of this study was to mathematically evaluate the effect of URAT1 inhibition with verinurad on intracellular lactate concentration.A mathematical model of urate and lactate transport in the rat proximal tubule was adapted to simulate transport in humans. The transporter model was further adjusted to represent states of hyperuricemia and altered expression of uric acid transporters that likely occur in hyperuricemia. The transporter model was linked to a systems description of plasma uric acid and the pharmacokinetics and pharmacodynamics of verinurad were incorporated into the model.The model was able to reproduce observed verinurad pharmacokinetics, as well as the observed changes in plasma and urinary uric acid. The model predicted that URAT1 inhibition with verinurad increases intracellular lactate concentration in the human PT by 26% in normouricemic and 20% in hyperuricemic conditions.Model simulations indicate that verinurad may substantially increase the availability of lactate inside PT epithelial cells. Since lactate is used as a fuel by the PT, increased availability of lactate may potentially help restore protein reabsorption capacity in fuel‐deficient PT cells by increasing ATP levels. In addition, increased intracellular lactate could help maintain the low endosomal pH necessary for protein reabsorption. This hypothesis remains to be experimentally proven; further non‐clinical/clinical data would be valuable to support model predictions.Urate and lactate proximal tubule transport model.Figure 1
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