The aim of the present study was to investigate the pharmacokinetic and pharmacodynamic characteristics of febuxostat following the administration of single and multiple oral doses under fasting conditions to healthy individuals. Thirty-six healthy subjects were randomly divided into three groups, each containing 12 subjects (six male and six female) as follows: Group A, treated with a single oral dose of febuxostat (40 mg); group B, treated with a single oral dose of febuxostat (80 mg) followed by multiple oral doses of febuxostat for 7 days; and group C, treated with a single oral dose of febuxostat (120 mg). Blood samples were collected, and the plasma drug levels and serum uric acid (UA) concentrations were determined by clinical laboratory testing. Febuxostat displayed a linear pharmacokinetic profile for oral doses of 40 to 120 mg. Drug accumulation was not detected following multiple oral doses. When febuxostat was administered as single doses of 40, 80 and 120 mg, the 24-h UA concentration (UA24) values displayed a linear correlation with the dosage. The relationship between UA24 and the three single dose levels (40, 80 and 120 mg) was analyzed. The difference in UA24 between every single dose was significant (P<0.05). After 3 and 7 days of dosing, reductions of 46.67 and 52.69%, respectively, were observed in UA24. On day 7 of dosing, the mean reduction in the UA concentration was 51.83±7.00%. This study demonstrates that febuxostat reduces serum UA concentrations in a dose-linear manner.

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The interplay between the Yamanaka factors (OCT4, SOX2, KLF4 and c-MYC) and transcriptional/epigenetic co-regulators in somatic cell reprogramming is incompletely understood. Here, we demonstrate that the histone H3 lysine 27 trimethylation (H3K27me3) demethylase JMJD3 plays conflicting roles in mouse reprogramming. On one side, JMJD3 induces the pro-senescence factor Ink4a and degrades the pluripotency regulator PHF20 in a reprogramming factor-independent manner. On the other side, JMJD3 is specifically recruited by KLF4 to reduce H3K27me3 at both enhancers and promoters of epithelial and pluripotency genes. JMJD3 also promotes enhancer-promoter looping through the cohesin loading factor NIPBL and ultimately transcriptional elongation. This competition of forces can be shifted towards improved reprogramming by using early passage fibroblasts or boosting JMJD3’s catalytic activity with vitamin C. Our work, thus, establishes a multifaceted role for JMJD3, placing it as a key partner of KLF4 and a scaffold that assists chromatin interactions and activates gene transcription.