PT  - JOURNAL ARTICLE
AU  - Agnès Poirier
AU  - Sara Belli
AU  - Christoph Funk
AU  - Michael B. Otteneder
AU  - Renée Portmann
AU  - Katja Heinig
AU  - Eric Prinssen
AU  - Stanley E. Lazic
AU  - Craig R. Rayner
AU  - Gerhard Hoffmann
AU  - Thomas Singer
AU  - David E. Smith
AU  - Franz Schuler
TI  - Role of the Intestinal Peptide Transporter PEPT1 in Oseltamivir Absorption: In Vitro and In Vivo Studies
AID  - 10.1124/dmd.112.044990
DP  - 2012 Aug 01
TA  - Drug Metabolism and Disposition
PG  - 1556--1565
VI  - 40
IP  - 8
4099  - http://dmd.aspetjournals.org/content/40/8/1556.short
4100  - http://dmd.aspetjournals.org/content/40/8/1556.full
SO  - Drug Metab Dispos2012 Aug 01; 40
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.