Abstract
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.
Footnotes
This study was supported in part by the Natural Science Foundation of Jiangsu Province [Grants BK2007169, BK2008038]; National Natural Science Foundation of China [Grants 30630076, 30801422]; and National Key New Drug Creation Special Program [Grants 2009ZX09304-001, 2009ZX09502-004].
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
doi:10.1124/dmd.110.033936.
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ABBREVIATIONS:
- G6P
- glucose 6-phosphate
- G6PD
- glucose-6-phosphate dehydrogenase
- UDPGA
- UDP-glucuronic acid
- LC
- liquid chromatography
- MS/MS
- tandem mass spectrometry
- PK
- pharmacokinetic
- GI
- gastrointestinal
- OCT
- organic cation transporter
- P-gp
- P-glycoprotein.
- Received April 14, 2010.
- Accepted July 15, 2010.
- Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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