| In Vitro | In vitro activity: Topiroxostat (formerly known as FYX-051; Brand names: Topiloric and Uriadec) is a novel and potent xanthine oxidoreductase (XOR) inhibitor which reduces serum urate levels and has IC50 value of 5.3 nM for XOR. It is a approved drug for the treatment of gout and hyperuricemia. It was initially approved in Japan in June 2013. Steady-state kinetics study showed that it initially behaved as a competitive-type inhibitor with a K(i) value of 5.7 × 10(-9) M, then after a few minutes it formed a tight complex with XOR via a Mo-oxygen-carbon atom covalent linkage, as reported previously (Proc Natl Acad Sci USA 101:7931-7936, 2004). Thus, FYX-051 is a hybrid-type inhibitor exhibiting both structure- and mechanism-based inhibition. The FYX-051-XOR complex decomposed with a half-life of 20.4 h, but the enzyme activity did not fully recover.
Kinase Assay: Steady-state kinetics study showed that FYX-051 initially behaved as a competitive-type inhibitor with a K(i) value of 5.7 × 10(-9) M, then after a few minutes it formed a tight complex with XOR via a Mo-oxygen-carbon atom covalent linkage, as reported previously |
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| In Vivo | FYX-051 exhibited a weak CYP3A4-inhibitory activity (18.6%); its Cmax and bioavailability were as high as 4.62 μg/mL (3 mg/kg) and 69.6%, respectively. Moreover, the t1/2 value of 39 was greater (19.7 h) than that of compound 2 (0.97 h). In the mechanistic study by 52-week oral treatment with topiroxostat at 3 mg/kg to F344 male rats, with and without citrate, simple and papillary transitional cell hyperplasias of the urinary bladder epithelium were observed in 5/17 in the topiroxostat-alone treatment group, along with xanthine-induced nephropathy, in contrast to neither xanthine crystals nor lesions in urinary organs by co-treatment group with citrate. |
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