title: Effects of topiroxostat and febuxostat on urinary albumin excretion and plasma xanthine oxidoreductase activity in db/db mice.
abstract: Topiroxostat, a xanthine oxidoreductase (XOR) inhibitor, has been shown to decrease the urinary albumin-to-creatinine ratio compared with placebo in hyperuricemic patients with stage 3 chronic kidney disease. Thus, we aimed to ascertain the albuminuria-lowering effect of topiroxostat in diabetic mouse. Db/db mice were fed standard diets with or without topiroxostat (0.1, 0.3, 1, and 3mg/kg/day) and febuxostat (0.1, 0.3, and 1mg/kg/day) for four weeks. Urinary albumin and purine bodies levels, XOR activities, and drug concentrations in the liver, kidney, and plasma were measured. Moreover, the XOR inhibitory activity of each XOR inhibitor was evaluated with or without an exogenous protein in vitro. Topiroxostat decreased dose-dependently the urinary albumin excretion, but febuxostat did not show such a tendency. Treatment with topiroxostat inhibited plasma XOR activity with dose-dependent increase in plasma purine levels, which was not observed by febuxostat. Pharmacokinetic/pharmacodynamic analysis revealed that topiroxostat and febuxostat concentration in each tissue showed a good correlation with both the hypouricemic effect and plasma drug concentration, whereas the change in albuminuria correlated neither with the change in uric acid nor with drug concentration in plasma. However, the change in urinary albumin and plasma XOR activity showed good correlation in topiroxostat group. The 50% inhibitory concentration (IC50 value) of febuxostat against plasma XOR in vitro was 12-fold higher than that of topiroxostat, and increased by approximately 13-fold by interfering with an exogenous protein. Topiroxostat caused reduced urinary albumin excretion, in which potent inhibition of the plasma XOR activity might be involved.
authors.affiliation: Pharmacological Study Group, Pharmaceutical Research Laboratories, Sanwa Kagaku Kenkyusho, Mie, Japan. Electronic address: ta_nakamura@mb4.skk-net.com.
authors.forename: Takashi
authors.initials: T
authors.lastname: Nakamura
authors.affiliation: Radioisotope and Chemical Analysis Center, Laboratory Management Department, Sanwa Kagaku Kenkyusho, Mie, Japan.
authors.forename: Takayo
authors.initials: T
authors.lastname: Murase
authors.affiliation: Pharmacological Study Group, Pharmaceutical Research Laboratories, Sanwa Kagaku Kenkyusho, Mie, Japan.
authors.forename: Mai
authors.initials: M
authors.lastname: Nampei
authors.affiliation: Pharmacological Study Group, Pharmaceutical Research Laboratories, Sanwa Kagaku Kenkyusho, Mie, Japan.
authors.forename: Nobutaka
authors.initials: N
authors.lastname: Morimoto
authors.affiliation: Research Department, Medical R&D Division, Fuji Yakuhin, Saitama, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Ashizawa
authors.affiliation: Research Department, Medical R&D Division, Fuji Yakuhin, Saitama, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Iwanaga
authors.affiliation: Project Management Department, Sanwa Kagaku Kenkyusho, Aichi, Japan.
authors.forename: Ryusuke
authors.initials: R
authors.lastname: Sakamoto
mesh_terms: D000419:Albuminuria / Q000652:urine*; D000818:Animals; D003928:Diabetic Nephropathies / Q000097:blood / Q000201:enzymology / Q000652:urine; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D000069465:Febuxostat / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D051379:Mice; D009570:Nitriles / Q000493:pharmacokinetics / Q000494:pharmacology*; D011725:Pyridines / Q000493:pharmacokinetics / Q000494:pharmacology*; D014968:Xanthine Dehydrogenase / Q000037:antagonists & inhibitors* / Q000097:blood*
chemical_list: D004791:Enzyme Inhibitors; D009570:Nitriles; D011725:Pyridines; C504882:FYX-051; D000069465:Febuxostat; D014968:Xanthine Dehydrogenase
keywords: Albuminuria; Diabetic nephropathy; Topiroxostat; Xanthine oxidoreductase