Abstract
Oseltamivir, an ester-type prodrug of the neuraminidase inhibitor [3R,4R,5S]-4-acetamido-5-amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate phosphate (Ro 64-0802), has been developed for the treatment of A and B strains of the influenza virus but has neuropsychiatric and other side effects. In this study, we characterized the transport across intestinal epithelial cells and the absorption of oseltamivir in rats. Uptake by Caco-2 cells (human carcinoma cell line) and HeLa cells transfected with peptide transporter 1 (HeLa/PEPT1) was time- and temperature-dependent and was inhibited by typical PEPT1 inhibitors such as glycyl-sarcosine (Gly-Sar). The uptake by Caco-2 cells and HeLa/PEPT1 was saturable, with similar Km values. Oseltamivir absorption in adult rats was greatly reduced by simultaneous administration of milk, casein, or Gly-Sar. Furthermore, the plasma and brain concentrations of oseltamivir were higher in fasting than in nonfasting rats after oral administration. These results suggest that oseltamivir is a substrate of PEPT1 and that PEPT1 is involved in its intestinal absorption.
Footnotes
-
This work was supported in part by a grant-in-aid for scientific research from the Ministry of Education, Science, and Culture, Japan.
-
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
-
doi:10.1124/dmd.109.026922.
-
ABBREVIATIONS: PEPT1, peptide transporter1; Ro 64-0802, [3R,4R,5S]-4-acetamido-5-amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate phosphate; P-gp, P-glycoprotein; MDR, multidrug resistance (or resistant); DMEM, Dulbecco's modified Eagle's medium; HBSS, Hanks' balanced salt solution; FBS, fetal bovine serum; Gly-Sar, glycyl-sarcosine; BNPP, bis(4-nitrophenyl) phosphate; TEER, transepithelial electrical resistance; AUC0–6h, area under the plasma concentration-time curve from time 0 to 6 h; BA, bioavailability.
- Accepted May 11, 2009.
- Received January 28, 2009.
- The American Society for Pharmacology and Experimental Therapeutics
DMD articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|