Pharmaceutical Research

, Volume 23, Issue 12, pp 2768–2780

Mechanisms Responsible for Poor Oral Bioavailability of Paeoniflorin: Role of Intestinal Disposition and Interactions with Sinomenine

Research Paper

DOI: 10.1007/s11095-006-9100-8

Cite this article as:
Liu, Z.Q., Jiang, Z.H., Liu, L. et al. Pharm Res (2006) 23: 2768. doi:10.1007/s11095-006-9100-8

Abstract

Purpose

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.

Results

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.

Conclusions

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 words

bioavailability Caco-2 disposition efflux intestinal paeoniflorin p-glycoprotein inhibitor sinomenine 

Copyright information

© Springer Science + Business Media, Inc. 2006

Authors and Affiliations

  1. 1.Department of Pharmacological and Pharmaceutical Sciences, College of PharmacyUniversity of HoustonHoustonUSA
  2. 2.School of Chinese MedicineHong Kong Baptist UniversityKowloon TongPeople’s Republic of China

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