Abstract
Berberine, one of the most commonly used natural products, exhibits poor plasma concentration-effect relationship whose underlying mechanisms remain largely unclear. This study was designed to test the hypothesis that extensive first-pass elimination and abundant tissue distribution of berberine may be its specific pharmacokinetic properties. For that, four different dosing routes ?intragastric (IG), intraduodenal (ID), intraportal (IPV) and intravenous (IV)- were utilized to investigate the gastric, intestinal, and hepatic first-pass elimination of berberine, respectively. After IG dosing, approximately half of berberine run intact through the gastrointestinal tract and another half was disposed of by the small intestine, leading to an extremely low extent of absolute oral bioavailability in rats (0.36%). Moreover, the major berberine metabolites were identified and quantified in rat enterocyte S9 fractions, portal vein plasma, and intestinal perfusates; plasma concentrations and tissue distribution of berberine and its major metabolites were determined as well. Data indicated that M1, M2-glucuronide, and M3 were the major metabolites generated from the small intestine, and that there was a 70-fold increase in the ratio of the AUC0-t value of berberine (liver vs. plasma). We conclude that intestinal first-pass elimination of berberine is the major barrier of its oral bioavailability, and that its high extraction and distribution in the liver could be another important cause that leads to its low plasma levels in rats.
Footnotes
- Received April 22, 2010.
- Accepted July 15, 2010.
- The American Society for Pharmacology and Experimental Therapeutics