This 10-day (D) study was conducted to evaluate changes in traditional and newer kidney safety biomarker expression levels in dogs. Animals received cisplatin (CDDP, 0.75 mg per kg per day) or 0.9% Saline (vehicle) for 5 days. Serum/urine samples were collected at various time points. Cage-side observations included emesis (D1-2/D4-D5/D7-9), absence of stool (D5-9/D11), soft stool (D4-7/D12), excessive salivation (D1/D3/D5-6), decreased food consumption (D5-8), decreased activity (D7-8) and/or dehydration (D7). Animals were necropsied when serum creatinine (sCr) levels measured at ≥1.9 mg dL, indicating significant loss of renal function; or at the end of the study (D11). When compared to controls, increases in BUN/sCr were detected on D3, D5 and/or D8. Increases in urinary total protein (Ur TP) were noted on D6. The moribund dog that was euthanized early on D7 showed insignificant increases in urinary osteopontin (Ur OPN), urinary neutrophil gelatinase-associated lipocalin (Ur NGAL), urinary clusterin (Ur CLU), sCr, serum cystatin C (sCYS C) and urinary cystatin C (Ur CYS C) on D5 when compared to controls. Insignificant increases in urinary albumin (Ur ALB) were observed from an animal that was euthanized on D7 and 1 : 2 surviving animals on D8 relative to baseline. From three dogs that were euthanized on D9, increases in Ur CLU, and/or sCYS C were noted on D8 relative to baseline. The two surviving dogs showed elevated Ur CLU and 1 : 2 surviving dogs showed elevated Ur CYS C. Decreased urinary kidney injury molecule 1 (Ur KIM-1) on D3/D5 was evident ( baseline and controls). CDDP-induced cortico-medullary lesions were characterized as minimal to mild tubule degeneration/necrosis, dilatation, regeneration, cell alteration, intratubular casts, interstitial inflammation and vacuolization. Increased Ur OPN and Ur CLU correlated with enhanced OPN and CLU immunopositive staining in damaged cortical epithelium in the proximal tubules. Enhanced KIM-1 staining in damaged cortico-medullary tubular epithelium appeared in the absence of rises in Ur KIM-1. This study showed changes in kidney safety protein biomarkers associated with CDDP nephrotoxicity in dogs and possibly in humans.

Background Control of blood uric acid is important for the treatment of gout. The clinical potential of a selective uric acid transporter 1 (URAT1) inhibitor as a drug for hyperuricemia and gout remains unknown because currently available uricosuric drugs block renal uric acid reabsorption by inhibiting not only URAT1 but also other transporters responsible for renal tubular uric acid secretion, such as OAT1 or OAT3. We have identified a highly selective URAT1 inhibitor, UR-1102, which is now under clinical trial for gout. Objectives In this study, we examined the therapeutic potential of selective URAT1 inhibition with UR-1102 by comparing it with benzbromarone, a traditional non-selective URAT1 inhibitor, in vitro and in vivo with cebus monkeys, an animal model that has similar purine metabolism and urinary uric acid excretion to humans. Methods The inhibitory effects of UR-1102 and benzbromarone on URAT1, OAT1, OAT3 and ABCG2 were evaluated in vitro using CHO cells that over-express these transporters. UR-1102 at 3, 10, and 30 mg/kg or benzbromarone at 3, 10, 30, and 100 mg/kg were administered orally once a day to cebus monkeys for 3 consecutive days (n=6, cross-over study). Plasma and urinary excretion of uric acid and creatinine were measured at regular time intervals. Fractional excretion of uric acid (FEUA) was calculated from those values. Results UR-1102 exhibited significantly more potent and highly selective (Ki values for URAT1 were >100 smaller than other transporters) URAT1 inhibition than benzbromarone in vitro, while benzbromarone inhibited URAT1, OAT1, OAT3 and ABCG2 dose-dependently as reported in the literature. The average plasma uric acid concentration for the control group was 3.6 +/- 0.2 mg/dL and FEUA was 8.8% +/- 0.4% on day 3 (0–8 hours after 3rd administration) in the cebus monkeys. Benzbromarone showed dose-dependent and significant reduction of plasma uric acid concentration (3.4, 3.0, 2.8, and 2.7 mg/dL at 3, 10, 30, and 100 mg/kg, respectively) and increase of FEUA (10.3%, 14.5%, 18.5%, and 20.6% at 3, 10, 30, and 100 mg/kg, respectively). UR-1102 also showed the dose-dependent and significant effects on plasma uric acid reduction (2.5, 2.4, and 1.8 mg/dL at 3, 10, and 30 mg/kg, respectively) and increase of FEUA (22.6%, 35.4%, and 42.1% at 3, 10, and 30 mg/kg, respectively). The effects were more apparent for UR-1102 at a lower dose. Moreover, comparing the submaximal dose of UR-1102 at 30 mg/kg with benzbromarone at 100 mg/kg, the effects were significantly higher for UR-1102 than for benzbromarone (plasma uric acid concentration: 1.8 +/- 0.2 mg/dL vs 2.7 +/- 0.2 mg/dL, p<0.01 and FEUA: 42.1% +/- 4.4% vs 20.6% +/- 2.3%, p<0.05). Conclusions Hypouricemic and uricosuric effects were more potent for UR-1102 than for benzbromarone in both dose and maximum efficacy in cebus monkeys. This may be due to the high selectivity of UR-1102 for URAT1. UR-1102 would have greater efficacy as a therapeutic drug for gout/hyperuricemia than benzbromarone. Disclosure of Interest S. O. Ah...