RT Journal Article
SR Electronic
T1 Metabolism of the Influenza Neuraminidase Inhibitor Prodrug Oseltamivir in the Rat
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 737
OP 741
VO 28
IS 7
A1 Sweeny, David J.
A1 Lynch, Geoffrey
A1 Bidgood, Alison M.
A1 Lew, Willard
A1 Wang, Ke-Yu
A1 Cundy, Kenneth C.
YR 2000
UL http://dmd.aspetjournals.org/content/28/7/737.abstract
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