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 K m 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.Various transporters are expressed on apical and basolateral membranes of intestinal epithelial cells, serving to take up nutrients and to excrete xenobiotics into the lumen. Influx transporters are able to accept nutrients and also various drugs as substrates. In particular, peptide transporter 1 (PEPT1, SLC15A1), localized at brush-border membranes of human small intestine (Saito et al., 1995), plays important roles in the absorption of not only di-/tripeptides (Tamai et al., 1994) but also peptide-mimetic compounds, such as orally administered ␤-lactam antibiotics (Ganapathy et al., 1995;Sai et al., 1996) and the anticancer agent bestatin (Tomita et al., 1990;Inui et al., 1992). Several researchers recently found that intestinal PEPT1 can transport L-valine ester prodrugs, such as valacyclovir and valganciclovir (Balimane et al., 1998;Han et al., 1998;Sugawara et al., 2000). Therefore, such structural modification of drugs may result in increased intestinal absorption, mediated by PEPT1.Oseltamivir phosphate (oseltamivir), manufactured under the trade name Tamiflu as an ester-type prodrug of the neuraminidase inhibitor Ro 64-0802, has been developed for the treatment of A and B strains of the influenza virus. This drug has been reported to be associated with neuropsychiatric side effects (http://www.fda.gov/cder/drug/ infopage/tamiflu/QA20051117.htm and http://www.mhlw.go.jp/ english/index.html), which are likely to be caused by distribution of oseltamivir and/or its metabolite(s) to the central nervous system. We recently examined the possible role of P-glycoprotein (P-gp) as the determinant of brain distribution of oseltamivir and Ro 64-0802 both in vitro using LLC-GA5-COL150 cells, which overexpress human multidrug resistance (or resistant) 1 (MDR1) P-gp on the apical membrane, and in vivo using mdr1a/1b knockout mice (Morimoto et al., 2008). The permeability of oseltamivir in the basolateral-to-apical dire...

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