Abstract
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.
Footnotes
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Send reprint requests to: Dr. David J. Sweeny, Gilead Sciences, Inc., 353 Lakeside Dr., Foster City, CA 94404. E-mail:David-Sweeny{at}Gilead.com
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↵1 Current address: Roche Discovery Welwyn, Hertfordshire, UK.
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↵2 Current address: Xenoport, Palo Alto, CA.
- Abbreviations used are::
- GS4071
- [2-acetyl-14C]oseltamivir
- LC-MS
- liquid chromatography-mass spectrometry
- SCX
- strong cation exchange
- Received July 7, 1999.
- Accepted March 28, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
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