TY - JOUR T1 - Extensive Intestinal First-Pass Elimination and Predominant Hepatic Distribution of Berberine Explain Its Low Plasma Levels in Rats JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 1779 LP - 1784 DO - 10.1124/dmd.110.033936 VL - 38 IS - 10 AU - Yi-Tong Liu AU - Hai-Ping Hao AU - Hong-Guang Xie AU - Li Lai AU - Qiong Wang AU - Chang-Xiao Liu AU - Guang-Ji Wang Y1 - 2010/10/01 UR - http://dmd.aspetjournals.org/content/38/10/1779.abstract N2 - Berberine, one of the most commonly used natural products, exhibits a 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, intraduodenal, intraportal, and intravenous, were used to investigate the gastric, intestinal, and hepatic first-pass elimination of berberine. After intragastric dosing, approximately half of berberine ran 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 area under the concentration-time curve value for berberine (liver versus 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 other important factors that lead to its low plasma levels in rats. ER -