Mechanisms Responsible for Poor Oral Bioavailability of Paeoniflorin: Role of Intestinal Disposition and Interactions with Sinomenine
To determine the intestinal disposition mechanisms of paeoniflorin, a bioactive glucoside, and to investigate the mechanisms by which sinomenine increases paeoniflorin bioavailability.
Materials and Methods
A single-pass “four-site” rat intestinal perfusion model and a cultured Caco-2 cell model were employed.
In both model systems, paeoniflorin permeability was poor. In the perfusion model, maximal absorption and metabolism of paeoniflorin occurred in duodenum and jejunum, which were significantly decreased by a glucosidase inhibitor gluconolactone (20 mM). On the other hand, paeoniflorin absorption in terminal ileum increased significantly but its metabolism did not in the presence of sinomenine and cyclosporine A. In the Caco-2 cell model, paeoniflorin was transported 48-fold slower than its aglycone (paeoniflorigenin). Absorptive transport of paeoniflorin was significantly (p < 0.05) increased by sinomenine (38%), verapamil (27%), and cyclosporine A (41%), whereas its secretory transport was significantly (p < 0.01) decreased by sinomenine (50%), verapamil (35%) and cyclosporine A (37%). In contrast, MRP inhibitors MK-571 and leukotriene C4 did not affect transport of paeoniflorin. Lastly, sinomenine was also shown to significantly increase the absorptive transport of digoxin (a prototypical p-glycoprotein substrate) and to significantly decrease its secretory transport.
Poor permeation, p-gp-mediated efflux, and hydrolysis via a glucosidase contributed to the poor bioavailability of paeoniflorin. Sinomenine (an inhibitor of the p-gp-mediated digoxin efflux) increased paeoniflorin's bioavailability via the inhibition of p-gp-mediated paeoniflorin efflux in the intestine.
Key wordsbioavailability Caco-2 disposition efflux intestinal paeoniflorin p-glycoprotein inhibitor sinomenine
This work was supported by grants (ZQL, LL, ZHJ) of JCICM-6-02 from the Hong Kong Jockey Club Charities Trust of Hong Kong and of CA-87779 (MH) from the National Institutes of Health, USA. This work was conducted at University of Houston, College of Pharmacy during a research visit by ZQL. The authors wish to thank Drs. Hong Xi Xu and Hua Zhou for their supports and comments to this work.
- 2.M. Kimura, I. Kimura, and H. Nojima. Depolarizing neuromuscular blocking action induced by electropharmacological coupling in the combined effect of paeoniflorin and glycyrrhizin. Jpn. J. Pharmacol. 37:395–397 (1984).Google Scholar
- 10.Y. Z. Shu, M. Hattori, T. Akao, K. Kobashi, K. Kagi, K. Fukuyama, T. Tsukihara, and T. Namba. Metabolism of paeoniflorin and related compounds by human intestinal bacteria. II. Structures of 7S-and 7R-paeonimetabolines I and II formed by Bacteroides fragillis and Lactobacillus brevis. Chem. Pharm. Bull. 35:2733– 3726 (1987).PubMedGoogle Scholar
- 13.L. Liu, J. Riese, K. Resch, and V. Kaever. Impairment of macrophage eicosanoid and nitric oxide production by sinomenine, an alkaloid from Sinomenium acutum. Arzneim.-Forsch. 44(11):1223–1226 (1994).Google Scholar
- 14.B. Vieregge, K. Resch, and V. Kaever. Synergistic effects of the alkaloid sinomenine in combination with the immunosuppressive drugs tacrolimus and mycophenolic acid. Planta Med. 44:1223–1226 (1999).Google Scholar
- 17.M. Hu, J. Chen, Y. Zhu, A. H. Dantzig, R. E. Stratford, and M. T. Kuhfeld. Mechanism and kinetics of transcellular transport of a new β-lactam antibiotic loracarbef across an human intestinal epithelial model system (Caco-2). Pharm. Res.(NY) 11:1405–1413 (1994).Google Scholar
- 20.E. J. Jeong, Y. Liu, H. Lin, and M. Hu. In situ single-pass perfused rat intestinal model for absorption and metabolism. In Z. Yan and G. W. Caldwell (eds.), In Methods in Pharmacology and Toxicology: Optimization in Drug Discovery—In Vitro Methods, Human, Totowa, NJ, 2004, pp. 65–76.Google Scholar
- 23.T. Tanaka, S. Takase, and T. Goda. A possible role of a nuclear factor NF-LPH1 in the regional expression of lactase-phlorizin hydrolase along the small intestine. J. Nutr. Sci. Vitaminol. (Tokyo) 43:565–573 (1997).Google Scholar