P-glycoprotein-mediated transport of berberine across Caco-2 cell monolayers.
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 degrees C compared with 37 degrees 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 (P(app)) of berberine was observed for B-A transport over a concentration range of 5-300 microM, indicating that the K(m) value of berberine for the carrier system is greater than 300 microM. 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 microM 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.
Maeng
Han-Joo
HJ
Department of Pharmaceutics, College of Pharmacy, Seoul National University, Seoul 151-742, Korea.
Yoo
Ho-Jung
HJ
Kim
In-Wha
IW
Song
Im-Sook
IS
Chung
Suk-Jae
SJ
Shim
Chang-Koo
CK
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000502:physiology*; D001599:Berberine / Q000737:chemistry / Q000493:pharmacokinetics*; D001692:Biological Transport; D018938:Caco-2 Cells / Q000378:metabolism*; D003630:Daunorubicin / Q000493:pharmacokinetics; D006801:Humans
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D001599:Berberine; D003630:Daunorubicin