Involvement of intestinal efflux and metabolic instability in the pharmacokinetics of platycodin D in rats.

We aimed to investigate the underlying mechanisms for low bioavailability of Platycodin D (PD) in rats. The bioavailability of PD was 1.89% with different half-lives depending on the administration route (2.14 ± 0.18 h for intravenous injection vs 5.42 ± 1.9 h for oral administration). The mean absorption time was 6.3 h calculated from the mean residence time of both administration routes. Consistent with these parameters, rat intestinal permeability using 3 different intestinal segments showed a low but greatest permeability in lower ileum (0.05 × 10-6  cm/s in jejunum and upper ileum vs 0.13 × 10-6  cm/s in lower ileum). The involvement of efflux system, probably Mrps, in upper ileum, could be explained from the efflux ratio of 6.4 and reduced efflux ratio by an Mrp inhibitor, MK571. The recovery of unchanged PD after the intravenous and oral administration was 50% and 5.2%, respectively, suggesting the contribution of gastrointestinal metabolism. In the gastrointestinal content, 4 metabolites of PD were identified: acetylated PD (m/z 1265.6), deglucose PD (m/z 1061.5), deapiose PD (m/z 1091.5), and deapiose-dexylose-derhamnose PD (m/z 813.4). In conclusion, the intestinal first-pass effect such as the presence of efflux functions in the upper ileum, limited but steady intestinal permeability, and gastrointestinal metabolism could explain the low bioavailability and prolonged absorption time of orally administered PD.