AB1023 Enhanced renal transporter activities of oat1 and oat3 by keishibukuryogan (K-06) and in vivo uric acid modulating effect at potassium oxonate-induced mouse setting
Authors: D.-S. Oh, H.J. Shin, S.H. Lee, S.-M. Oh
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Studies on renal solute carrier transporters have made the renal pathophysiology be in progress towards more mechanistic and the knowledge on renal drugs including drug-drug interaction be more evidentiary. Among the evidence, uricosuric phenomenon has been known that rodent experimental model is also useful for predicting human uricosuria. <h3>Objectives</h3> The aim of this study was to assess the substrate uptake at the overexpression of renal transporters, OAT1, OAT3 and URAT1 at kidney proximal tubular cell lines with or without a commercial herbal medicine, Keishibukuryogan (K-06) and to further measure serum and urinary uric acid concentrations in the setting of potassium oxonate (PO)-induced ICR mouse model with or without K-06. <h3>Methods</h3> The transporter-expressed HEK293-OAT1 and HEK293-OAT3 cells were seeded on BD poly-d-lysine microplates to uptake the [<sup>3</sup>H] estrone sulfate for 5 min in absence or presence of K-06. URAT1 was overexpressed using Xenopus oocytes being injected with <i>in vitro</i>-copied RNA of URAT1, and then to measure the uptake of [<sup>14</sup>C] uric acid with/without K-06. Total radioactivity was measured using a liquid scintillation counter. Serum and urinary uric acid was measured in PO ICR mice after three-day intake of K-06. They were assigned by 4 per each group; 1) control group, 2) PO-induced group, 3) PO-induced with allopurinol 50 mg/kg/day intake group and 4) PO-induced with allopurinol plus K-06 300 mg/kg/day intake group. <h3>Results</h3> To determine the kinetic parameters of concentration-dependent uptake of overexpressed OAT1 and OAT3 transporters in HEK293 cells, the K-06 inhibitory parameters on OAT1 and OAT3 were presented with the IC<sub>50</sub> values of 49.3 and 31.5 µg/mL, respectively. The K-06 inhibited URAT1 with IC<sub>50</sub> of 59.3 µg/mL. The K-06 (300 mg/kg) reduced serum levels of uric acid approximately 30% compared to that of PO-control group (p=0.039) and K-06 showed the slight elevation of urinary uric acid by 12% compared to that of PO-control group with no statistical significance. <h3>Conclusions</h3> The present findings demonstrated that the K-06 modulated basolateral and apical renal transporters and the K-06 showed the slight increased uric acid excretion and the uric acid lowering effect in experimental mouse setting. <h3>References</h3> [1] Becker GJ, Hewitson TD. Animal models of chronic kidney disease: useful but not perfect. Nephrol Dial Transplant2013;28:2432–8. doi: 10.1093/ndt/gft071 [2] Key difference between mouse and human kidney cells. Which isavailable at https://www.sciencedaily.com/releases/2016/03/160318181600.htm <h3>Acknowledgements</h3> This study was supported by the Traditional Korean Medicine R and D program funded by the Ministry of Health and Welfare through the Korea Health Industry Development Institute (KHIDI, Grant # HI16C0864). The commercial herbal products, Keishibukuryogan (K-06) were donated by the virtue of Kracie Pharma, Co., Ltd. <h3>Disclosure of Interest</h3> None declared