Mikiko Tsukimoto

Sialoglycoproteins that bind influenza A virus and resist viral neuraminidase in different animal sera

Sialoglycoproteins that are resistant to degradation by viral neuraminidase can effectively neutralize influenza A viruses, because they bind irreversibly to the viruses. To detect such proteins in animal sera, we developed an immunochemical assay based on Western blotting techniques. We assessed the binding activity of sialoglycoproteins in sera from nine different animals toward the A/Aichi/2/68 (H3N2) and A/PR/8/34 (H1N1) strains of influenza virus, with or without viral and bacterial neuraminidase treatment. Using this assay, we found that animal sera contain a spectrum of sialoglycoproteins defined by differing abilities to bind influenza A viruses and to resist the viral neuraminidase. Structural analysis of these inhibitors would provide useful information for the development of anti-influenza virus compounds.

Effects of the inhibition of intestinal P‐glycoprotein on aliskiren pharmacokinetics in cynomolgus monkeys

Aliskiren is a substrate for P‐glycoprotein (P‐gp) and is metabolized via cytochrome P450 3A4 (CYP3A4). The aim of the present study was to assess whether P‐gp influenced the pharmacokinetics of aliskiren and also if drug–drug interactions (DDIs) mediated through P‐gp could be reproduced in cynomolgus monkeys. The study investigated the pharmacokinetics of aliskiren in mdr1a/1b gene‐deficient (P‐gp KO) and wild‐type (WT) mice. The area under the plasma concentration–time curve (AUC) following the oral administration of aliskiren was 6.9‐fold higher in P‐gp KO mice than in WT mice, while no significant differences were observed in the AUC or total plasma clearance following the intravenous administration of aliskiren to P‐gp KO mice. Then the pharmacokinetics of aliskiren were evaluated and DDIs between aliskiren and P‐gp inhibitors, such as cyclosporin A (CsA) and zosuquidar, examined in cynomolgus monkeys. The AUC for aliskiren were 8.3‐ and 42.1‐fold higher after the oral administration of aliskiren with the concomitant oral administration of zosuquidar and CsA at doses of 10 and 30 mg/kg, respectively. In contrast, the AUC after the intravenous and oral administration of aliskiren was not significantly affected by the oral administration of zosuquidar or intravenous administration of CsA, respectively. These results indicated that P‐gp strictly limited the intestinal absorption of aliskiren in mice and monkeys, and also that the effects of intestinal P‐gp inhibition by CsA or zosuquidar on the pharmacokinetics of aliskiren were sensitively reproduced in monkeys. In conclusion, aliskiren can be used as a sensitive substrate to evaluate intestinal P‐gp inhibition in monkeys. Copyright