Metabolism of the influenza neuraminidase inhibitor prodrug oseltamivir in the rat.
The metabolism of [2-acetyl-(14)C]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)-omega-carboxylic acid metabolite of oseltamivir. The omega-carboxylic acid metabolite of oseltamivir could not be produced in vitro. However, omega-hydroxylated products of oseltamivir were produced by rat liver microsomes. Both the (R)- and (S)-omega-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)-omega-carboxylic acid metabolite.
Sweeny
D J
DJ
Gilead Sciences, Inc., Foster City, California 94404, USA. David_Sweeney@Gilead.com
Lynch
G
G
Bidgood
A M
AM
Lew
W
W
Wang
K Y
KY
Cundy
K C
KC
D000081:Acetamides / Q000493:pharmacokinetics*; D000818:Animals; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics*; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D009439:Neuraminidase / Q000037:antagonists & inhibitors*; D053139:Oseltamivir; D011355:Prodrugs / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012015:Reference Standards; D014018:Tissue Distribution
D000081:Acetamides; D004791:Enzyme Inhibitors; D011355:Prodrugs; D053139:Oseltamivir; D009439:Neuraminidase