P-Glycoprotein–Mediated Transport of Berberine across Caco-2 Cell Monolayers

• Published in: Journal of pharmaceutical sciences 2002-12, Vol.91 (12), p.2614-2621
• Main Authors: Maeng, Han-Joo, Yoo, Ho-Jung, Kim, In-Wha, Song, Im-Sook, Chung, Suk-Jae, Shim, Chang-Koo
• Format: Article
• Language: English
• Subjects: ATP-Binding Cassette, Sub-Family B, Member 1 - antagonists & inhibitors; ATP-Binding Cassette, Sub-Family B, Member 1 - physiology; berberine; Berberine - chemistry; Berberine - pharmacokinetics; Biological and medical sciences; Biological Transport; Caco-2 cell monolayers; Caco-2 Cells - metabolism; Daunorubicin - pharmacokinetics; Digestive system; Humans; Medical sciences; P-gp; Pharmacology. Drug treatments; transport
• ISSN: 0022-3549; 1520-6017
• DOI: 10.1002/jps.10268

The objective of this study was to investigate the mechanisms by which berberine is transported in the secretory and absorptive directions across Caco-2 cell monolayers. The basolateral-to-apical (B-A) flux was 30-fold greater than the apical-to-basolateral flux and temperature dependent (i.e., drastic decrease at 4°C compared with 37°C). The above results suggest the involvement of a carrier-mediated active transport mechanism for the B-A transport of berberine. However, no significant concentration dependency for the permeability (Papp) of berberine was observed for B-A transport over a concentration range of 5–300 μM, indicating that the Km value of berberine for the carrier system is greater than 300 μM. Well-documented P-glycoprotein (P-gp) substrates such as verapamil, daunomycin, and rhodamine123 inhibited the B-A flux of berberine, whereas tetraethylammonium and taurocholate did not, suggesting that P-gp is involved in the transport. For the case of daunomycin, the B-A flux, but not the apical-to-basolateral flux, was significantly increased after pretreatment of the cell monolayers with berberine. In addition, the uptake of 1 μM daunomycin into Caco-2 cells was decreased as a result of this pretreatment. These results suggest that the repeated administration of berberine may up-regulate P-gp functions in Caco-2 cells. If this occurs in the gastrointestinal epithelial cells, the repeated administration of berberine may reduce the gastrointestinal absorption of P-gp substrates including chemotherapeutic agents such as daunomycin. © 2002 Wiley-Liss, Inc. and the American Pharmaceutical Association