GS-5806 is an inhibitor of human respiratory syncytial virus with potent antiviral activity against a broad range of clinical isolates and efficacy in animal models of infection. In this study we determined tissue distribution, mass balance, metabolite profiling of GS-5806 and its distribution into the epithelial lining fluid (ELF) in rats.
[14C] GS-5806 was orally dosed in rats at 10 mg/kg. Radioactivity in whole blood, plasma, urine, and feces was analyzed using liquid scintillation counting. Radioactivity in tissues was analyzed using quantitative whole body autoradiography. Metabolite profiling was performed using HPLC-radiometry and mass spectrometry.
For the lung penetration study, bronchoalveolar lavage fluid samples and lung tissues were collected. Samples were analyzed by LC MS/MS with endogenous urea used as the dilution marker to convert the bronchoalveolar lavage to the epithelial lung fluid levels.
Majority of the circulating radioactivity in plasma was associated with unchanged GS-5806. N-acetylated metabolite was the prevalent circulating metabolite identified in plasma followed by a minor metabolite resulting from reductive deamination. The major route of elimination was via biliary excretion. The prevalent route of metabolism of GS-5806 in rats was via reductive deamination and N-acetylation. Subsequent steps included oxidation, decarboxylation, and sulfation. [14C] GS-5806 related radioactivity in the upper and lower respiratory tract tissues of the rat significantly exceeded the blood levels. GS-5806 demonstrated significant penetration into ELF (19 fold over plasma levels) and lung tissues (87 fold).
GS-5806 was cleared in rats via a combination of direct elimination and metabolic processes with GS-5806 being primary circulating species in plasma and major component in feces and urine. The studies demonstrate that GS-5806 exhibits favorable lung distribution and therapeutic levels in the upper and lower respiratory tract are expected to be easily achievable following an oral dose.
Gilead Sciences, Inc.:
R. Mackman, Gilead Sciences: Employee and Shareholder , Salary
M. Perron, Gilead Sciences: Employee and Shareholder , Salary