Pharmacokinetics and disposition of CS-8958, a long-acting prodrug of the novel neuraminidase inhibitor laninamivir in rats

Xenobiotica. 2010 Mar;40(3):207-16. doi: 10.3109/00498250903447691.

Abstract

CS-8958, a prodrug of laninamivir (R-125489), is currently under development as an inhaled anti-influenza drug. In this study, the pharmacokinetics and disposition of CS-8958 were characterized in rats. After intratracheal administration of 14C-CS-8958, radioactivity was retained over long periods in the target tissues (trachea and lung) as its active metabolite R-125489 - 19.12% of the dose was retained in the lung at 24 h. After intratracheal administration of CS-8958, plasma R-125489 concentration was slowly eliminated, and its half-life (14.1 h) was considerably longer than that after intravenous administration of R-125489. The radioactivity of intratracheally administered 14C-CS-8958 was mainly excreted into the urine (67.5% of dose), and this excretion lasted over long periods. R-125489 accounted for most of the urinary radioactivity recovered after 24 h. These results demonstrated that CS-8958 administered intratracheally to rats was converted/hydrolysed to R-125489 in the target tissues, and that the R-125489 was slowly excreted into the urine via an absorption rate-limiting process. Such distinctive pharmacokinetics attributed to the slow release of R-125489 suggests the potential for a long-acting anti-influenza drug.

MeSH terms

  • Animals
  • Antiviral Agents / pharmacology*
  • Bile / chemistry
  • Chromatography, Thin Layer
  • Enzyme Inhibitors / administration & dosage
  • Enzyme Inhibitors / analysis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacokinetics*
  • Feces / chemistry
  • Guanidines
  • Male
  • Neuraminidase / antagonists & inhibitors*
  • Prodrugs / administration & dosage
  • Prodrugs / analysis
  • Prodrugs / chemistry
  • Prodrugs / pharmacokinetics*
  • Pyrans
  • Radioactivity
  • Rats
  • Rats, Sprague-Dawley
  • Sialic Acids
  • Time Factors
  • Tissue Distribution / drug effects
  • Tissue Extracts
  • Zanamivir / administration & dosage
  • Zanamivir / analogs & derivatives*
  • Zanamivir / analysis
  • Zanamivir / chemistry
  • Zanamivir / pharmacokinetics
  • Zanamivir / pharmacology

Substances

  • Antiviral Agents
  • CS 8958
  • Enzyme Inhibitors
  • Guanidines
  • Prodrugs
  • Pyrans
  • Sialic Acids
  • Tissue Extracts
  • laninamivir
  • Neuraminidase
  • Zanamivir