Evaluation of the non-linearity of NA808 in liver not reflected in plasma using a rat pharmacokinetic study and PBPK modelling.

When NA808, a potent HCV replication inhibitor, was intravenously administered to rats, it was distributed to the liver. The AUC ratio in the liver of 20 mg/kg to 2 mg/kg was greater than the dose ratio, whereas exposure in plasma was increased in a dose-proportional manner. Saturation of biliary excretion was also shown at 20 mg/kg.NA808 was revealed to be a substrate for both OATP1B and MRP2 transporters by an in vitro study using OATP1B1-MRP2 expressing cells. [14C]NA808 was taken up into the cells by OATP1B1 and excreted from cells by MRP2 efficiently (Papp ratio: 24.2-70.2). The Papp ratio decreased with increasing NA808 concentration.PBPK modelling was constructed to display the blood and liver concentration time profile and biliary excretion of NA808. This model analysis was able to reproduce the pharmacokinetics in rats; the degree of increase in the liver exposure from 2 to 20 mg/kg was more than dose-proportional and was greater than the increase in the blood exposure due to saturation of efflux transporters.In drug development, to avoid unexpected toxicity in tissues, it is important to consider the potential for tissue non-linearity with linear plasma exposure based on pre-clinical data and PBPK modelling.

Self-enhancement of hepatitis C virus replication by promotion of specific sphingolipid biosynthesis.

Lipids are key components in the viral life cycle that affect host-pathogen interactions. In this study, we investigated the effect of HCV infection on sphingolipid metabolism, especially on endogenous SM levels, and the relationship between HCV replication and endogenous SM molecular species. We demonstrated that HCV induces the expression of the genes (SGMS1 and 2) encoding human SM synthases 1 and 2. We observed associated increases of both total and individual sphingolipid molecular species, as assessed in human hepatocytes and in the detergent-resistant membrane (DRM) fraction in which HCV replicates. SGMS1 expression had a correlation with HCV replication. Inhibition of sphingolipid biosynthesis with a hepatotropic serine palmitoyltransferase (SPT) inhibitor, NA808, suppressed HCV-RNA production while also interfering with sphingolipid metabolism. Further, we identified the SM molecular species that comprise the DRM fraction and demonstrated that these endogenous SM species interacted with HCV nonstructural 5B polymerase to enhance viral replication. Our results reveal that HCV alters sphingolipid metabolism to promote viral replication, providing new insights into the formation of the HCV replication complex and the involvement of host lipids in the HCV life cycle.

Development of an amorphous selenium-based photodetector driven by a diamond cold cathode.

Amorphous-selenium (a-Se) based photodetectors are promising candidates for imaging devices, due to their high spatial resolution and response speed, as well as extremely high sensitivity enhanced by an internal carrier multiplication. In addition, a-Se is reported to show sensitivity against wide variety of wavelengths, including visible, UV and X-ray, where a-Se based flat-panel X-ray detector was proposed. In order to develop an ultra high-sensitivity photodetector with a wide detectable wavelength range, a photodetector was fabricated using a-Se photoconductor and a nitrogen-doped diamond cold cathode. In the study, a prototype photodetector has been developed, and its response to visible and ultraviolet light are characterized.