TY - JOUR T1 - Metabolism of the Influenza Neuraminidase Inhibitor Prodrug Oseltamivir in the Rat JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 737 LP - 741 VL - 28 IS - 7 AU - David J. Sweeny AU - Geoffrey Lynch AU - Alison M. Bidgood AU - Willard Lew AU - Ke-Yu Wang AU - Kenneth C. Cundy Y1 - 2000/07/01 UR - http://dmd.aspetjournals.org/content/28/7/737.abstract N2 - The metabolism of [2-acetyl-14C]oseltamivir (GS4104, Ro 64-0796), the prodrug of the novel influenza neuraminidase inhibitor GS4071 (Ro 64-0802), was examined in rats after oral dosing. Intact oseltamivir was observed only in lung and urine, accounting for 37 and 15% of the total radioactivity in these samples, respectively. GS4071 was the major metabolite in plasma, tissues, and urine, and accounted for 32 to 56% of the radioactivity present in these samples. The second most abundant peak in these samples (13–24% of radioactivity) was a novel metabolite (M3). This metabolite was purified from urine of rats dosed orally with oseltamivir and was identified by liquid chromatography-mass spectrometry and NMR as the (R)-ω-carboxylic acid metabolite of oseltamivir. The ω-carboxylic acid metabolite of oseltamivir could not be produced in vitro. However, ω-hydroxylated products of oseltamivir were produced by rat liver microsomes. Both the (R)- and (S)-ω-hydroxylated products were observed, but formation of the (R)-isomer predominated. These data indicated that in the rat, oseltamivir was primarily metabolized to the active influenza neuraminidase inhibitor GS4071 and, to a lesser extent, to an (R)-ω-carboxylic acid metabolite. The American Society for Pharmacology and Experimental Therapeutics ER -