Effect of ion-pair formation with bile salts on the in vitro cellular transport of berberine

Abstract

The objective of this study was to examine the effect of ion-pair complexation with endogenous bile salts on the transport of a quarternary ammonium organic cationic (OC) drug, berberine, across the Caco-2 and LLC-PK1 cell monolayers. The basolateral-to-apical (BL-AP) transport of berberine in Caco-2 cells was temperature dependent and 10-fold higher than that of the apical-to-basolateral (AP-BL) transport. Similar results were observed for the transport of berberine across the LLC-PK1 cells. Moreover, the BL-AP transport in the Caco-2 cells was significantly reduced by the cis-presence of P-glycoprotein (P-gp) inhibitors such as cyclosporine A, verapamil, and digoxin. These results suggest that an efflux transporter, probably P-gp, is involved in the Caco-2 cell transport. The K m and V max values for the carrier-mediated transport were estimated to be 83.4 mM and 7640 pmole/h/cm 2 , respectively. The apparent partition coefficient (APC) of berberine between n-octanol and a phosphate buffer (pH 7.4) was increased by the presence of an organic anion (OA), taurodeoxycholate (TDC, a bile salt), suggesting the formation of a lipophilic ion-pair complex between an OC (berberine) and an OA (TDC). Despite the ion-pair complexation, however, the BL-AP transport of berberine across the Caco-2 and LLC-PK1 cells was not altered by the cis-presence of bile salts or the rat bile juice. This is consistent with the reportedly unaltered secretory transport of a quarternary ammonium compound, tributylmethylammonium (TBuMA), across the Caco-2 cell monolayers in the cis-presence of bile salts or the rat bile juice, but not with our previous report in which the secretory transport of TBuMA across the LLC-PK1 cell was increased in the cis-presence of TDC. Therefore, the effect of ion-pair formation with the bile components or bile salts on the secretory transport of OCs appears to depend on the molecular properties of OCs (e.g., molecular weight, lipophilicity and affinity to relevant transporters) and the characteristics of cell strains (e.g., expression and contribution of responsible transporters to the transport).

Formation and Conformation of Baicalin–Berberine and Wogonoside–Berberine Complexes

“…The increased lipophilicity of the complex is expected to contribute positively to the bioavailability of these pharmacologically active constituents. 11) On the other hand, efflux transporters are involved in the cell transport of berberine and baicalin, 17,18) it is speculated that the baicalin-berberine and wogonosideberberine complexes, differing greatly in their hydrophobicity and confirmation, may exhibit quite different affinities for the relevant transporters, and consequently result in distinct pharmacokinetic behavior from that of single compounds. Moreover, binding to DNA, in which process the quaternary ammonium cation and planar structure of berberine play a critical role, is well-known to be closely associated with its biological activities and anti-cancer mechanisms.…”

Berberis aristata/Silybum marianumfixed combination on lipid profile and insulin secretion in dyslipidemic patients

“…Nevertheless of its biological functions, berberine is anyway rather defective in terms of oral bioavailability [16]; it is affected by a P-glycoprotein (P-gp)-mediated gut extrusion process [17]. P-gp seems to reduce the amount of berberine capable of crossing the enterocytes by about 90% and this suggest that the use of a potential P-gp inhibitor [18] could ameliorate its oral poor bioavailability, thus improving its effectiveness. Among the potential P-gp inhibitors, silymarin from Silybum marianum, herbal drug traditionally used as liver protectant [19], could be considered a good candidate [20] due to its very poor oral bioavailability and its very high safety profile [21].…”

Pilot study on the additive effects of berberine and oral type 2 diabetes agents for patients with suboptimal glycemic control

“…In humans, this appears to be due to a P-glycoprotein-mediated gut extrusion process18 and substantial excretion in bile 19. P-glycoprotein seems to decrease the amount of berberine able to cross enterocytes by about 90%,20 suggesting that inhibition of P-glycoprotein could potentially improve its oral poor bioavailability. Among the potential P-glycoprotein inhibitors, silymarin from Silybum marianum could be a good candidate due to its very poor oral bioavailability and its good safety profile 21…”