Pharmacokinetics, Pharmacodynamics and Drug MetabolismEffect of Milk on the Pharmacokinetics of Oseltamivir in Healthy Volunteers
Section snippets
INTRODUCTION
Dietary constituents may influence drug response in various ways, ranging from loss of efficacy to toxicity. In particular, interactions that modify drug absorption may be of clinical importance because drug effects are dependent on the concentration of the active species at the site of action. The absorption process itself may be influenced by drug-metabolizing enzymes as well as by influx and efflux transporters expressed in the small intestine. For example, it is well known that dietary
Study Design
A randomized, open-label, two-period, crossover clinical pharmacokinetic study was conducted. Six healthy male Japanese volunteers aged 21–25 were enrolled. An evaluation before the study showed that the subjects had unremarkable medical history, and normal findings on physical examination and standard clinical laboratory tests (general hematology, blood chemistry). The study was conducted in compliance with the Declaration of Helsinki. All individuals gave written informed consent for the
Plasma Concentration
Figure 1 shows the plasma concentration–time profiles of oseltamivir and Ro 64-0802 after a single oral dose of 75 mg oseltamivir (as 98 mg phosphate salt) with either 400 mL of water or 400 mL of milk. The pharmacokinetic parameters of oseltamivir and Ro 64-0802 are summarized in Table 1. In the case of coadministration with water, Cmax was 38.2 ng/mL at 1.4 h after administration, whereas AUC0–2, AUC2–4, AUC0–24, and AUC0–∞ were 47.6, 32.8, 109, and 114 ng·h/mL, respectively. In the case of
DISCUSSION
Our clinical study showed that milk reduced the total absorption of oseltamivir, estimated by adding the urinary recovery of oseltamivir and Ro 64-0802, to 77.5% of the control. However, the plasma concentration of Ro 64-0802 at 12 h after administration (C12), an index of anti-influenza virus effect,13 was not significantly different between the two treatments. This suggests that no dose adjustment is required when oseltamivir is administered with milk.
Although the effects of milk in humans
CONCLUSION
Our results indicate that milk inhibited the intestinal absorption of oseltamivir in humans. However, the extent of interaction in humans was limited as compared with that in rats, possibly because of species difference in the regional expression of PEPT1 in the small intestine and/or differences in the contribution of other absorption mechanisms. Among PEPT1 substrates, it seems likely that compounds whose absorption would be largely completed within the transit time of the duodenum may show
Acknowledgements
This study was supported by a grant from the Research Foundation for Pharmaceutical Sciences, and by government grants-in-aid for scientific research.
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