Biodistribution and pharmacokinetic profile of berberine and its metabolites in hepatocytes
Abstract
Background Berberine has been shown in clinical studies to have many health benefits, including anti-inflammatory and antioxidant properties, along with gut-flora balancing properties. However, its clinical efficacy is hindered by its low oral bioavailability and rapid metabolism.Purpose This study aims to identify the berberine metabolites' forms and characterize their biodistribution patterns in and out of HepG2 cells.Methods The qualitative analysis of metabolites of berberine in HepG2 cells was performed using the LC/MS n-IT-TOF method. Subsequent cellular pharmacokinetics characterization of intracellular and extracellular berberine and its metabolites was performed by LC-MS/MS analysis.Results Berberine's metabolites of phase I metabolism were demethyleneberberine, jatrorrhizine, columbamine, berberrubine, etc., while its phase II metabolites were sulfate and glucuronide conjugates of phase I metabolites. Among the phase I metabolites of berberine, jatrorrhizine+columbamine accounted for over two-thirds of the total, followed by demethyleneberberine, which accounted for about a quarter. The intracellular demethyleneberberine is 25.14 times more enriched than extracellular demethyleneberberine. On the other hand, jatrorrhizine+columbamine and berberrubine were primarily distributed extracellularly, and their extracellular concentrations were 7.13 times and 15.61 times of their intracellular concentrations, respectively. Berberine metabolites produced in phase II metabolism are predominantly sulfate conjugates.Conclusion Our results show that demethyleneberberine is highly concentrated intracellularly in HepG2, possibly because it is an essential metabolite of berberine that likely contributes to berberine's efficacy. In light of our findings, berberine's poor plasma concentration-effectiveness characteristics have been partially explained.
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Berberine and its metabolites are themselves substrates and/or inhibitors of several enzymes and transporters, broadening the spectrum of interactions.
“Berberine and its metabolites (berberrubine, thalifendine, demethyleneberberine, and jatrorrhizine), formed predominantly by CYP1A2, CYP2D6 and CYP3A4, are themselves substrates and/or inhibitors of several enzymes and transporters, which broadens the spectrum of interactions [59,60,61].”
From Berberine-Drug Interactions: Mechanisms, Clinical Relevance and Risk Stratification-A Narrative Review (2026) · cites this paper as [60]
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- Authors
- Liu, X., Li, W., Zhang, H., Wang, X., Huang, Y., Li, Y., & Pan, G.
- Affiliations
- Tianjin University of Traditional Chinese Medicine (CN)
- Corresponding author
- Wang, Xiaoming
- Pan, Guixiang
- Venue
- Phytomedicine
- Publisher
- Elsevier BV
- Published
- 2022-09
- Volume
- 104
- Pages
- 154288
- ISSN
- 0944-7113 (ISSN-L)
- OpenAlex
- W4283119138
- Cited by
- 27
- References
- 31
- Citations by year
- 2026: 8 · 2025: 6 · 2024: 5 · 2023: 8
- FWCI
- 2.84
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- Phytomedicine (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Tianjin Research Innovation Project for Postgraduate Students (2021YJSB287)
- National Natural Science Foundation of China (81173523, 81303182)
- National Key Research and Development Program of China (2021YFC1712900)
- Topics
- Health Sciences › Medicine › Pharmacology › Berberine and alkaloids research
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Keywords
- berberine, jatrorrhizine, columbamine, berberrubine, phase I metabolism, phase II metabolism, sulfate conjugates, glucuronide conjugates, subcellular localization, HepG2 cells, hepatocytes, cellular pharmacokinetics, oral bioavailability
- MeSH terms
- Berberine, Chromatography, Liquid, Humans, Sulfates, Tissue Distribution, Tandem Mass Spectrometry, Hep G2 Cells
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