Oseltamivir (tamiflu) is a substrate of peptide transporter 1.
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.
Laboratory of Biopharmaceutics, Department of Pharmacology, Faculty of Pharmacy, Takasaki University of Health and Welfare, 60 Nakaorui, Takasaki, Gunma, Japan. togihara@takasaki-u.ac.jp
Takuo
T
Ogihara
Takashi
T
Kano
Tamae
T
Wagatsuma
Sho
S
Wada
Hikaru
H
Yabuuchi
Shigeki
S
Enomoto
Kaori
K
Morimoto
Yoshiyuki
Y
Shirasaka
Shoko
S
Kobayashi
Ikumi
I
Tamai
D000284:Administration, Oral; D000818:Animals; D000831:Animals, Newborn; D000998:Antiviral Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D001692:Biological Transport; D001921:Brain / Q000378:metabolism; D018938:Caco-2 Cells; D002364:Caseins / Q000378:metabolism; D004151:Dipeptides / Q000494:pharmacology; D005260:Female; D018565:Food-Drug Interactions; D006367:HeLa Cells; D006801:Humans; D007408:Intestinal Absorption / Q000187:drug effects; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008892:Milk / Q000378:metabolism*; D053139:Oseltamivir / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D000074011:Peptide Transporter 1; D051381:Rats; D017208:Rats, Wistar; D027981:Symporters / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D013696:Temperature; D014162:Transfection
D000998:Antiviral Agents; D002364:Caseins; D004151:Dipeptides; D000074011:Peptide Transporter 1; C082186:SLC15A1 protein, human; C489940:Slc15a1 protein, rat; D027981:Symporters; D053139:Oseltamivir; C004194:glycylsarcosine; C016810:tryptophylglycine