Conclusions
The underlying mechanism of the improved pharmacokinetic profile of amenamevir was linked to an improved absorption ratio (not hepatic availability) compared to acyclovir, and qualitative differences in elimination (slow metabolism of amenamevir vs rapid urinary excretion of acyclovir/valaciclovir).
Methods
In situ absorption, blood and plasma radioactivity concentrations, tissue distribution, and excretion were determined using liquid scintillation counting. Plasma amenamevir concentrations were measured using a validated chromatographic method. Chemical structures of in vivo metabolites were investigated using liquid chromatography-mass spectrometry and nuclear magnetic resonance spectroscopy.
Results
Amenamevir, after single intravenous administration to mice, had an elimination half-life of 2 h. Bioavailability was 40% after single oral administration. In situ absorption data indicated that amenamevir is mainly absorbed in the small intestine. The main component in mouse plasma was amenamevir, accounting for 87.9% of amenamevir-derived components. Our results suggest that the main elimination pathway in mice is oxidative metabolism at a methyl group and a 1,2,3-trisubstituted benzene ring followed by biliary and fecal excretion. Following oral administration of 14C-amenamevir to mice, 100.63% of the dose (10.06% in urine and 90.46% in feces) was excreted by 96 h post-dose. Conclusions: The underlying mechanism of the improved pharmacokinetic profile of amenamevir was linked to an improved absorption ratio (not hepatic availability) compared to acyclovir, and qualitative differences in elimination (slow metabolism of amenamevir vs rapid urinary excretion of acyclovir/valaciclovir).