Abstract
It was recently reported that oseltamivir (Tamiflu®) absorption was mediated by hPEPT1. 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 (CHO-K1) and human PEPT1-transfected cells (CHO-hPEPT1), 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-hPEPT1 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 glycyl-sarcosine (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, following 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 following 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 or human PEPT1 in the oral absorption of oseltamivir.
- antivirals
- drug absorption
- drug transport
- drug-drug interactions
- intestinal transport
- oral absorption
- pharmacokinetics
- prodrugs
- transporters
- Received February 14, 2012.
- Accepted May 14, 2012.
- The American Society for Pharmacology and Experimental Therapeutics