RT Journal Article
SR Electronic
T1 Role of the Intestinal Peptide Transporter PEPT1 in Oseltamivir Absorption: In Vitro and In Vivo Studies
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 1556
OP 1565
DO 10.1124/dmd.112.044990
VO 40
IS 8
A1 Poirier, Agnès
A1 Belli, Sara
A1 Funk, Christoph
A1 Otteneder, Michael B.
A1 Portmann, Renée
A1 Heinig, Katja
A1 Prinssen, Eric
A1 Lazic, Stanley E.
A1 Rayner, Craig R.
A1 Hoffmann, Gerhard
A1 Singer, Thomas
A1 Smith, David E.
A1 Schuler, Franz
YR 2012
UL http://dmd.aspetjournals.org/content/40/8/1556.abstract
AB It was reported that oseltamivir (Tamiflu) absorption was mediated by human peptide transporter (hPEPT) 1. Understanding the exact mechanism(s) of absorption is important in the context of drug-drug and diet-drug interactions. Hence, we investigated the mechanism governing the intestinal absorption of oseltamivir and its active metabolite (oseltamivir carboxylate) in wild-type [Chinese hamster ovary (CHO)-K1] and hPEPT1-transfected cells (CHO-PEPT1), in pharmacokinetic studies in juvenile and adult rats, and in healthy volunteers. In vitro cell culture studies showed that the intracellular accumulation of oseltamivir and its carboxylate into CHO-PEPT1 and CHO-K1 was always similar under a variety of experimental conditions, demonstrating that these compounds are not substrates of hPEPT1. Furthermore, neither oseltamivir nor its active metabolite was capable of inhibiting Gly-Sar uptake in CHO-PEPT1 cells. In vivo pharmacokinetic studies in juvenile and adult rats showed that the disposition of oseltamivir and oseltamivir carboxylate, after oral administration of oseltamivir, was sensitive to the feed status but insensitive to the presence of milk and Gly-Sar. Moreover, oseltamivir and oseltamivir carboxylate exhibited significantly higher exposure in rats under fasted conditions than under fed conditions. In humans, oral dosing after a high-fat meal resulted in a statistically significant but moderate lower exposure than after an overnight fasting. This change has no clinical implications. Taken together, the results do not implicate either rat Pept1 or hPEPT1 in the oral absorption of oseltamivir.