PT  - JOURNAL ARTICLE
AU  - David J. Sweeny
AU  - Geoffrey Lynch
AU  - Alison M. Bidgood
AU  - Willard Lew
AU  - Ke-Yu Wang
AU  - Kenneth C. Cundy
TI  - Metabolism of the Influenza Neuraminidase Inhibitor Prodrug Oseltamivir in the Rat
DP  - 2000 Jul 01
TA  - Drug Metabolism and Disposition
PG  - 737--741
VI  - 28
IP  - 7
4099  - http://dmd.aspetjournals.org/content/28/7/737.short
4100  - http://dmd.aspetjournals.org/content/28/7/737.full
SO  - Drug Metab Dispos2000 Jul 01; 28
AB  - 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