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

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.

• Authors: K Koyama, M Takahashi, N Nakai, H Takakusa, T Murai, M Hoshi, N Yamamura, N Kobayashi, O Okazaki
• Journal: Xenobiotica; the fate of foreign compounds in biological systems (Xenobiotica) Vol. 40 Issue 3 Pg. 207-16 (Mar 2010) ISSN: 1366-5928 [Electronic] England
• PMID: 20146556 (Publication Type: Journal Article)

Chemical References

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

Topics

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