Pharmacokinetic and bioequivalence study between two formulations of S-1 in Korean gastric cancer patients.

PURPOSE: S-1 is an oral fluoropyrimidine anticancer drug consisting of the 5-fluorouracil prodrug tegafur combined with gimeracil and oteracil. The purpose of this study was to evaluate the pharmacokinetic (PK), bioequivalence, and safety of a newly developed generic formulation of S-1 compared with the branded reference formulation, in Korean gastric cancer patients. METHODS: This was a single-center, randomized, open-label, single-dose, two-treatment, two-way crossover study. Eligible subjects were randomly assigned in a 1:1 ratio to receive the test formulation or reference formulation, followed by a one-week washout period and administration of the alternate formulation. Serial blood samples were collected at 0 hrs (predose), 0.25, 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, and 48 hrs after dosing in each period. The plasma concentrations of tegafur, 5-FU, gimeracil, and oteracil were analyzed using a validated liquid chromatography-tandem mass spectrometry method. The PK parameters were calculated using a non-compartmental method. RESULTS: In total, 29 subjects completed the study. All of the 90% confidence intervals (CIs) of the geometric mean ratios (GMRs) fell within the predetermined acceptance range. No serious adverse events were reported during the study. CONCLUSION: The new S-1 formulation met the Korean regulatory requirement for bioequivalence. Both S-1 formulations were well tolerated in all subjects.Clinical trial registry: https://cris.nih.go.kr CRIS KCT0003855.

Magnesium chenoursodeoxycholic acid ameliorates carbon tetrachloride-induced liver fibrosis in rats.

This study was designed to investigate the hepatoprotective effects of magnesium chenoursodeoxycholic acid (Mg-CUD), a magnesium trihydrate salt of ursodeoxycholic acid and chenodeoxycholic acid, in carbon tetrachloride (CCl(4))-induced liver fibrosis in rats. Rats were treated with CCl(4) dissolved in olive oil (0.5 mL/kg, twice a week) intraperitoneally for eight weeks. Mg-CUD was administered orally at 15.625, 31.25, 62.5 and 125 mg/kg once a day. Chronic CCl(4) administration induced increases in serum transforming growth factor-ß1, hepatic hydroxyproline content and serum alanine aminotransferase activity. Mg-CUD attenuated these increases. The levels of α-smooth muscle actin protein and mRNA expression were increased by chronic CCl(4) exposure and Mg-CUD attenuated these increases. Mg-CUD suppressed increases in matrix metalloproteinase-2 and tissue inhibitor of metalloproteinase-1 mRNA expression and elevation of oxidative stresses by attenuating lipid peroxidation and enhancing reduced glutathione/oxidized glutathione ratio. The overexpression of toll-like receptor 4 and increased nuclear translocation of nuclear factor-κB and phosphorylated c-Jun, a component of activator protein 1, were suppressed by Mg-CUD. Furthermore, CCl(4) increased the levels of tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-10 and cyclooxygenase (COX)-2. Mg-CUD attenuated the levels of TNF-α, IL-6 and COX-2, while it augmented the level of IL-10. Our results suggest that Mg-CUD may prevent liver fibrosis by modulating collagen accumulation and inflammatory signaling pathways.

Protective effects of Mg-CUD against D-galactosamine-induced hepatotoxicity in rats.

This study examined the protective effects of magnesium chenoursodeoxycholic acid (Mg-CUD), a magnesium trihydrate salt of chenodeoxycholic acid (CDCA) and ursodeoxycholic acid (UDCA), against D-galactosamine (D-GalN)-induced liver injury. Hepatotoxicity was induced by intraperitoneal injection of D-GalN (700mg/kg) and Mg-CUD (15.625, 31.25 and 62.5mg/kg) was administered orally once a day for 2weeks and 6h after D-GalN injection. Significant increases in the level of serum alanine aminotransferase activity and lipid peroxidation were attenuated by Mg-CUD 24h after D-GalN treatment. Hepatic glutathione/oxidized glutathione ratio was decreased, and this decrease was attenuated by Mg-CUD. Mg-CUD attenuated the increase in the levels of serum tumor necrosis factor (TNF)-α and interleukin (IL)-6, while it augmented the increase in serum IL-10 level and heme oxygenase (HO)-1 protein expression. Mg-CUD attenuated increased levels of TNF-α, IL-6, and IL-1ß mRNA expression. Increased levels of IL-10 and HO-1 mRNA expression were augmented by Mg-CUD. The increased nuclear level of nuclear factor-κB (NF-κB) and decreased cytosolic level of Inhibitory κB-α protein were attenuated by Mg-CUD. Nuclear phosphorylated c-Jun (p-c-Jun) level showed a significant increase and this increase was attenuated by Mg-CUD. Our results suggest that Mg-CUD ameliorates D-GalN-induced acute hepatitis and that this protection is likely due to its anti-oxidative and anti-inflammatory activities, and inhibition of NF-κB nuclear translocation and nuclear p-c-Jun expression.