RT Journal Article
SR Electronic
T1 Oseltamivir (Tamiflu) Is a Substrate of Peptide Transporter 1
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 1676
OP 1681
DO 10.1124/dmd.109.026922
VO 37
IS 8
A1 Takuo Ogihara
A1 Takashi Kano
A1 Tamae Wagatsuma
A1 Sho Wada
A1 Hikaru Yabuuchi
A1 Shigeki Enomoto
A1 Kaori Morimoto
A1 Yoshiyuki Shirasaka
A1 Shoko Kobayashi
A1 Ikumi Tamai
YR 2009
UL http://dmd.aspetjournals.org/content/37/8/1676.abstract
AB 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.