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.
Subject(s)
Antiviral Agents/pharmacology , Enzyme Inhibitors/pharmacokinetics , Neuraminidase/antagonists & inhibitors , Prodrugs/pharmacokinetics , Zanamivir/analogs & derivatives , Animals , Bile/chemistry , Chromatography, Thin Layer , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/analysis , Enzyme Inhibitors/chemistry , Feces/chemistry , Guanidines , Male , Prodrugs/administration & dosage , Prodrugs/analysis , Prodrugs/chemistry , Pyrans , Radioactivity , Rats , Rats, Sprague-Dawley , Sialic Acids , Time Factors , Tissue Distribution/drug effects , Tissue Extracts , Zanamivir/administration & dosage , Zanamivir/analysis , Zanamivir/chemistry , Zanamivir/pharmacokinetics , Zanamivir/pharmacologyABSTRACT
In aqueous solutions, the fluorescence of the intramolecular fluorescence resonance energy-transfer (FRET) system 1 was strongly quenched, because of close contact between the donor and acceptor moieties. FRET occurred, and the acceptor fluorescence was increased, by adding beta-cyclodextrin (beta-CD) to aqueous solutions of 1. Spectral analysis supported the idea that the FRET enhancement was due to the formation of an inclusion complex of the coumarin moiety in beta-CD, resulting in separation of the fluorophores. On the basis of this result, we propose that covalent binding of coumarin to beta-CD will provide a FRET cassette molecule. So, compound 2 bearing beta-CD covalently was designed and synthesized. Fluorescence intensity of 2 was enhanced markedly compared to the intensity of 3. Applying this FRET system, various FRET probes that will be useful for ratio imaging and also the high-throughput screening will be provided.
