Effect of Ion-Pair Formation with Bile Salts on the In Vitro Cellular Transport of Berberine
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1 Arch Pharm Res Vol 31, No 1, , 2008 DOI /s Effect of Ion-Pair Formation with Bile Salts on the In Vitro Cellular Transport of Berberine Hye-Won Chae 1,2, In-Wha Kim 1,2, Hyo-Eon Jin 1,2, Dae-Duk Kim 2, Suk-Jae Chung 2, and Chang-Koo Shim 1,2 1 National Research Laboratory for Transporters Targeted Drug Design, College of Pharmacy, Seoul National University, Seoul , Korea and 2 Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul , Korea (Received July 16, 2007) 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). Key words: Berberine, Ion-pair effect, P-Glycoprotein, Caco-2 transport, Taurodeoxycholate INTRODUCTION Correspondence to: Chang-Koo Shim, 1 National Research Laboratory for Transporters Targeted Drug Design, College of Pharmacy, Seoul National University, Seoul , Korea and 2 Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul , Korea Tel: , Fax: shimck@snu.ac.kr Berberine, an isoquinoline quarternary ammonium alkaloid isolated from the plants genera Berberis and Coptis, has anti-microbial, anti-diarrheic, and anti-inflammatory properties (Ckless et al., 1995; Kaneda et al., 1991; Taylor et al., 1999). Despite extensive literatures on the pharmacology, little is known about the pharmacokinetics and transport characteristics of the drug, except that the oral bioavailability in the beagle dog is low (Sheng et al., 1993) and it is a substrate of P-glycoprotein (P-gp), multidrug resistance associated protein (MRP1) (Maeng et al., 2002; Shitan et al., 2007), and organic cation transporters (OCTs) (Tsai and Tsai, 2004). In general, organic cations (OCs) form lipophilic ion-pair complexes in the presence of certain organic anions (OAs), especially deoxyconjugated bile salts, resulting in an increase in gastrointestinal absorption and percutaneous passage of the OCs (Gaginella et al., 1973, Lee et al., 1978, Shim et al., 1981, Shim et al., 1986, Neubert, 1989, Van Gelder et al., 1999). Our group reported that the ionpair complexes of a quarternary ammonium compound, tributylmethylammonium (TBuMA), with taurodeoxycholate (TDC), a bile salt, significantly increased the affinity of 103
2 104 H.-W. Chae et al. TBuMA to P-gp (760 M versus 16.1 M for K m, P<0.01) (Song et al., 2001). Physiologically, bile salts exist in the intestine via enterohepatic circulation (Dressman et al., 1998, Kalantzi et al., 2006); therefore, bile salts may affect intestinal absorption of berberine if ion-pair complexes are formed between berberine and the bile salts. We hypothesize that the formation of lipophilic ion-pair complexes with endogenous bile salts may be a contributing factor in the efflux transport of berberine across the intestinal membrane. The transport mechanism of berberine across the Caco-2 cell monolayer, as well as the effect of ion-pair complexation with endogenous bile salts on the transport, was investigated in this study. MATERIALS AND METHODS Materials Fetal bovine serum was purchased from Hyclone Laboratories (Logan, UT, U.S.A.). Trypsin-EDTA was purchased from Gibco Laboratories (Gaithersburg, MD, U.S.A.). The following items were purchased from Sigma Chemical Co. (St. Louis, MO, U.S.A.): Dulbecco's Modified Eagle's medium, non-essential amino acid solution, L-glutamine, penicillin-streptomycin (10,000 units/ml-10,000 g/ml), Hank s balanced salt solution (HBSS), N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid (HEPES), berberine sulfate, cyclosporine A, verapamil, digoxin, n-octanol, taurodeoxycholate (TDC), amomonium phosphate monobasic, and ammonium phosphate dibasic. All other reagents were of analytical grade. Determination of the apparent partition coefficients The apparent partition coefficient (APC) of berberine between aqueous and organic phases was measured as described in previous studies (Shim et al., 1981; Song et al., 2001). The n-octanol and a 0.1 M phosphate buffer solution (PBS, 0.05 M ammonium phosphate monobasic and 0.05 M ammonium phosphate dibasic, ph 7.4) were used as the organic and aqueous phases, respectively, for the partition study. The n-octanol and PBS were used after the presaturation with each other. Berberine and TDC were dissolved in the PBS (5 ml) to yield a final berberine concentration of 50 M and TDC concentrations of ~1000 M. The APC of berberine in the presence of bile (10%, v/v) was also measured. The bile was colleted from SD rats as previously described (Song et al., 2001). The 5 ml of the presaturated n-octanol was then added to each of the above described PBS solutions (5 ml), and the mixture was vortexed vigorously for 3 min. The mixture was shaken for 2 h at 25 o C in a water bath and was separated into two phases by centrifugation at 3,000 rpm for 10 min. The 100 L aliquot of the aqueous phase was taken, and the concentration of the berberine in each sample was determined by HPLC. Estimation of true partition coefficient, formation constant, and extraction constant of the ion-pair complex The APC of an ionic compound varies depending on the concentration of the compound and counterions, thereby giving limited information on the lipophilicity of corresponding ion-pair complexes. Therefore, some other parameters that can appropriately describe the characteristics of the ion-pair complexes become necessary to be determined. The true partition coefficient of the ion-pair complex (TPC) between the aqueous and n-octanol phases, the formation constant of the ion-pair complex (K f ) in the aqueous phase, and the extraction constant of a compound (K e ) from the aqueous phase to the n-octanol phase were determined using following equations that were developed previously by Shim et al. (1981). TPC = AB o (1) AB w K = AB w f (2) A+ w B- w AB o K e = = K (3) A+ w B- w f TPC da = A o + (4) A+ w APC = A o T (5) AT w Where brackets indicate molar concentrations and subscripts, o and w denote organic and aqueous phases, respectively, and da indicates the partition coefficient of cation A +. T denotes the total sum of the compound A (i.e., ionic form plus ion-pair complex form). The values of K e and TPC were estimated from the reciprocals of the intercept and the slope of the regression line obtained by plotting B T w /(APC da) versus {(B T w /da)/ (APC da)} + A T T w + B w in the following equation, and K f was estimated from the relationship of Eq. (3). B w T K e B wt 1 da A APC da APC da wt + BT 1 = w TPC Cell cultures The human colonic epithelial cell line, Caco-2 cells, and the porcine kidney epithelial cell line, LLC-PK1 cells, were obtained from American Type Culture Collection (Rockville, MD, U.S.A.) and grown as described in previous studies (Li et al., 2001; Song et al., 2003). The integrity of the cell monolayers was evaluated prior to the transport experiments by measuring transepithelial electrical resistance (6)
3 Effect of Ion-Pair Formation on the Transport of Berberine 105 (TEER) and/or the permeability of [ 14 C]mannitol across the monolayers. The transport experiment was performed when TEER values of the cell monolayers were in the ranges of cm 2 and cm 2 for the Caco-2 and LLC-PK1 cell monolayers, respectively, or the transport permeability values of [ 14 C]mannitol < cm/ sec. Transport study The transport characteristics of berberine was studied using an in vitro monolayer system of Caco-2 cells as previously described (Maeng et al., 2002). Before the transport experiment, the cell monolayers were washed three times with an transport medium (ph 7.4, HBSS containing 25 mm HEPES and 25 mm glucose). After each wash, the plates were incubated in the transport medium for 30 min at 37 o C, and the TEER value was measured (Li et al., 2001). The apical to the basolateral (AP- BL, absorptive) transport and the basolateral to the apical transport (BL-AP, secretory) were studied as previously described (Li et al., 2001). The concentration dependency of the transepithelial transport was examined for various concentrations of berberine (30 to 300 M for AP-BL and 3 to 300 M for BL-AP). To examine the effect of a rat bile or bile salts on the transepithelial transport of berberine, the transport medium containing berberine and the rat bile (10%) or TDC was added on the donor side, and the transport medium without berberine, bile or TDC was added on the receiver side of the insert as previously described (Song et al., 2003). Aliquots (100 L) were sampled from the receiver side at given time intervals for 30 min, and the concentration of the berberine in each sample was determined by HPLC. HPLC analysis The concentration of berberine in the sample was determined using a reversed phase HPLC method (Chen and Chang, 1995, Pan et al., 2002) after minor modification. The HPLC system consisted of Waters 717 plus autosampler and 515 HPLC dual pumps (Milford, MA, U.S.A.). The HPLC was performed using a C 18 column (XTerra TM, 250 mm 4.6 mm, 5 m, Waters). The mobile phase was a mixture of acetonitrile: 62 mm KH 2 PO 4 buffer (60:40) and 0.43% sodium dodecyl sulfate. The flow rate was maintained at 1 ml/min. A Waters 717 plus 2487 Dual l absorbance detector was operated at a wavelength of 267 nm for the analysis of TDC-containing samples. A Shimazu RF-535 fluorescence detector was operated at an excitation wavelength of 348 nm and an emission wavelength of 526 nm for the analysis of bile-containing samples. Data analysis In each transport experiment, the mean transport rate (pmol/h/cm 2 ) was calculated from the linear portion of a plot of the total amount of drug transported versus time. The apparent permeability values, P app, of the drug across the Caco-2 cell monolayers, expressed as cm/sec, were calculated as Q/ t 1/60 1/A 1/C 0, where Q/ t is the permeability rate (mmole/min), A is the surface area of the membrane (1 cm 2 ), and C 0 is the initial concentration of the drug in the donor chamber (mmole/ml) (Artursson and Karlsson, 1991). The flux-concentration data were analyzed according to the following equation with a nonlinear regression using a WinNonlin program (version 3.1; Pharsight Co., Mountainview, CA, U.S.A.). V V max = C (7) K m + C K C In this equation, V, V max, K m, K and C represent flux, maximum flux, Michaelis-Menten constant, linear rate constant, and the concentration of berberine in the donor compartment, respectively. The statistical significance of the differences between treatments was evaluated using the unpaired Student s t-test. A value of p < 0.05 was considered to be statistically significant. The data expressed as the mean ± SD of more than three experiments. RESULTS AND DISCUSSION Transport of berberine in Caco-2 cell monolayers The vectorial transport of berberine in the apical to basolateral (AP-BL, absorptive) direction and the basolateral to apical (BL-AP, secretory) direction was determined as a function of time. The secretory (i.e., BL-AP) transport was much faster than the absorptive (i.e., AP-BL) transport. The apparent permeability coefficient for the secretory transport (14.1 ± cm/s) was more than 10-fold larger than that of the absorptive permeability (1.36 ± cm/s), when measured at a initial berberine concentration of 100 M (Fig. 1). The effect of berberine concentration on the transport rate of the drug was then investigated. The absorptive transport (flux) increased almost linearly as a function of berberine concentration in the apical side over the concentration range of M, while the secretory transport (flux) increased in a concentration-dependent manner (Fig. 2). This is consistent with the idea that the absorptive transport is a passive process and the secretory transport is mediated by a carrier-mediated system in Caco-2 cells. The V max, K m, and CL int for the secretory transport were calculated by fitting the data to Eq. (7) to be 7640 ± 224 pmol/h/cm 2, 83.4 ± 5.76 M, and 91.6 ± 4.58 L/cm 2 /h, respectively, with a negligible clearance for the passive diffusion. The significant temperature-dependency in the secretory transport of berberine (Fig. 3B) supports the involvement of a carrier system in the transport. The K m
4 106 H.-W. Chae et al. Fig. 1. The apparent permeability of berberine at a concentration of 100 M across Caco-2 cell monolayers. Each data point represents the mean ± SD of three monolayers. Fig. 2. Concentration dependency of the apical to the basolateral (AP- BL, closed circle) and the basolateral to the apical (BL-AP, open circle) transport for the various concentrations of berberine across Caco-2 cell monolayers. Each data point represents the mean ± SD of three monolayers. The lines represent the best fit for the data by least square regression analysis using WinNolin software. value in this study is smaller than that (>300 M) obtained by Maeng et al. (2002). This discrepancy cannot be addressed satisfactorily at the moment, but the difference in the salt form of berberine (i.e., berberine sulfate in this study and berberine chloride in the study of Maeng et al.) might be associated with the mechanism, as implicated from the fact that berberine sulfate exhibits a substantially higher water solubility compared to berberine chloride. Effect of the bile and a bile salt, taurodeoxycholate (TDC), on the partitioning behavior of berberine The APC of berberine increased significantly by the copresence of bile (from zero to 7 for 10 M berberine in the Fig. 3. The effect of temperature on the apical to the basolateral transport (A) of 75 M berberine and the basolateral to the apical transport (B) of 15 M berberine across Caco-2 cell monolayers. Each point represents the mean ± SD of three monolayers. Closed and open bars indicate the absence and presence of taurodeoxycholate, respectively. *p<0.05, significantly different from the control (absence of taurodeoxycholate). presence of 10% bile) and as a function of TDC concentration ( M) (Fig. 4A). This is consistent with the hypothesis that a lipophilic ion-pair complex is formed between berberine and bile components or TDC. The TPC, K e and K f of for the berberine-tdc ion- pair complex were determined using Eqs. (1~3) assuming a 1:1 (berberine:tdc) formation of the complex (Shim et al., 1981). Using the data in Fig. 4A, [B T W/(APC da)] was plotted as a function of [B T W da/(apc da)+a T W + B T W] according to Eq. (6) (Fig. 4B). From the reciprocal of the y-axis intercept, a K e value of 18,500 M -1 was obtained. The linear regression of the plot resulted in a line with a slope of almost zero (Fig. 4B). It indicates that the true partition coefficient (TPC) of the berberine-tdc complex is too large to estimate. Because the value of TPC could not be estimated, the values of K f could not be estimated either from the relationship of Eq. (3).
5 Effect of Ion-Pair Formation on the Transport of Berberine 107 Fig. 4. (A) Effect of various concentrations of taurodeoxycholate on the apparent partition coefficient (APC) of 50 M berberine. (B) Plots of B T W/(APC da) versus B T W da/(apc da) +A T W + B T W for the ion-pair complexe of 50 M berberine with various concentrations of taurodeoxycholate. Here, A T W and B T W, are the total concentration of berberine and TDC in the aqueous phase, respectively, and da is the partition coefficient of berberine its self. The line represents the best fit for the data by linear least square regression analysis using WinNolin software. Each data point represents the mean ± SD of four experiments. Effect of the bile and TDC on the transport of berberine across the Caco-2 and LLC-PK1 cell monolayer The transepithelial transport of berberine across the Caco-2 cell and LLC-PK1 cell monolayer was measured as a function of time in the absence or presence of 10% rat bile. An increase in the BL-AP transport of berberine was expected by the co-presence of the bile, because the affinity of berberine to P-gp (most likely responsible for the secretory transport of berberine, Maeng et al., 2002) would have been increased by the formation of lipophilic ion-pair complexes with bile components (e.g., TDC, Song et al., 2003). The formation of ion-pair complexes was suggested by the increased APC of berberine in the presence of bile (from zero to 7 for 10 M berberine). However, no increase in the BL-AP transport of berberine was observed by the presence of bile (Fig. 5A). Instead, a slight increase in the AP-BL transporter was observed by the presence of the bile. This suggests that the passive diffusion, but not the P-gp mediated secretory transport, appears to be increased by the ion-pair complexation. The effect of ion-pair complexation with TDC on the transport of berberine across the Caco-2 cell monolayer was also examined. Contrary to the expectation that the secretory BL-AP transport of berberine (15 M) via P-gp would be increased through the ion-pair formation (as suggested by Fig. 4A), the transport was not increased but rather slightly decreased by the cis-presence of 150 M TDC (Fig. 3B and Fig. 6B). This result suggests that not only P-gp but also other transporters (e.g., organic cation transporters; OCTs, Tsai and Tsai, 2004) may be involved in the secretory transport of berberine. In the case of OCTs, the affinity of berberine to these transporters would be reduced by the ion-pair complexation because the positive charge of berberine would be masked by this reaction (Zhang et al., 1999), resulting in a decrease in the secretory transport of berberine. Similar studies were performed for the LLC-PK1 cell monolayer (Fig. 5B). The presence of rat bile (10%, Fig. 5B) or TDC (500 M, data not shown) had no effect on the secretory and absorptive transports. Because the bile salt export pump (Bsep) is not expressed in LLC-PK1 cells (Torok et al., 1999), the association of Bsep in this observation could be excluded. The involvement of P-gp in the secretory transport of berberine-tdc ion-pair complex across the cell membrane monolayer The passive diffusion of the berberine ion-pair complex with bile and TDC for both AP-BL and BL-AP directions was increased compared to that of berberine itself (Fig. 3 and Fig. 5), probably due to increased lipophilicity by the ion-pair complexation, which is consistent with previous reports (Gaginella et al., 1973; Lee et al., 1978; Neubert, 1989; Van Gelder et al., 1999). The involvement of P-gp in the secretory transport of total berberine (i.e., berberine plus berberine-tdc ion-pair complex) across the Caco-2 cell monolayer was examined by measuring the transport of berberine in the presence of P-gp inhibitors. The BL-AP transport of berberine (15 M) in the cis-presence of TDC (150 M) was inhibited to a significant extent (P<0.05) by the presence of representative P-gp inhibitors (i.e., 20 M cyclosporine A, 100 M verapamail, and digoxin) (Fig. 6B), with significant increase in the AP-BL transport (Fig. 6A), indicating that P-gp is obviously involved in the secretory transport of berberine even in the presence of TDC (i.e., in the presence of berberine-tdc ion-pair complex). Nevertheless, the secretory transport was not increased in the
6 108 H.-W. Chae et al. Fig. 5. The apical to the basolateral (AP-BL) and basolateral to the apical (BL-AP) transports of berberine in the absence (closed bar) or presence (open bar) of rat bile (10%) across the Caco-2 cell (A) and LLC-PK1 cell monolayers (B). The concentrations of berberine for the AP-BL and BL-AP transports were 10 and 3 M, respectively. Each point represents the mean ± SD of three monolayers. *p<0.05, significantly different from the control (i.e., absence of taurodeoxycholate). cis-presence of TDC in Caco-2 and LLC-PK1 cells (Fig. 5). This is contrary to our expectation that the secretory transport of berberine would be increased by the formation of the lipophilic ion-pair complex (i.e., berberine-tdc complex), which would demonstrate higher affinity to P-gp compared to berberine itself (Chiba et al., 1998; Klopman and Zhu, 2005; Song et al., 2001; Zamora et al., 1988). This is not consistent with the case for TBuMA either, in which the secretory transport of the compound across the LLC-PK1 cell monolayer was increased by the cis-presence of TDC (Song et al., 2001). It should be noted that the affinity of berberine (83.4 M, this study) to P-gp is much higher compared to TBuMA (760 M in clpm vesicles, Song et al., 2001). The high enough affinity of berberine to P-gp might have not been increased even in the presence of TDC (i.e., comparable Fig. 6. Effect of P-glycoprotein inbitibors (20 M cyclosporine, 100 M verapamil, and 100 M digoxin) on berberine permeation across Caco- 2 cell monolayers. The apical to the basolateral (A) and the basolateral to the apical (B) permeation of berberine (30 M for apical-tobasolateral and 15 M for basolateral-to-apical, respectively) was investigated in the presence ( ) and absence ( ) of 10-fold of taurodeoxycholate. Each point represents the mean ± SD of three monolayers. *p<0.05, the transport flux (with inhibitor) is significantly different from the control (without inhibitor). affinity to P-gp for the ion-pair complex and berberine itself). In the case of TBuMA, on the other hand, a significant increase in the affinity was observed by the ion-pair complexation (from 760 for TBuMA to 16.1 M for TBuMA-TDC ion-pair complex in clpm vesicles, Song et al., 2001). Therefore, the discrepancy between the effect of ion-pair complexation on the secretory transport of berberine and TBuMA across the LLC-PK1 cell monolayer might be associated with the difference in the lipophilicity or the affinity of these OCs to P-gp. Besides, the involvement of OCTs in the transport of
7 Effect of Ion-Pair Formation on the Transport of Berberine 109 Table I. Effect of the ion-pair complexation with taurodeoxycholate (TDC) on the secretory transport of organic cations (OCs) across the Caco-2 and LLC-PK1 cell monolayers Berberine TBuMA Caco-2 no effect 1) no effect 2) LLC-PK1 no effect 1) increase 3) OCs: M, TDC: 10-fold higher than those of OCs. 1) this study. 2) unpublished data. 3) Song et al. (2001). these OCs (Tsai and Tsai, 2004) might be associated with this discrepancy as well. Because the polarity of berberine is decreased by the ion-pair complexation, the affinity of berberine to OCTs would be reduced by the complexation (Zhang et al., 1999), resulting in a decrease in the OCTsmediated secretory transport of berberine, possibly offsetting the increase in the P-gp-mediated secretory transport of the drug. Therefore, the different contribution of OCTs and P-gp to the transport of berberine and TBuMA might be associated with the discrepancy between the secretory transport of these OCs across the LLC-PK1 cell monolayer in the presence of TDC. Our unpublished data demonstrate that the cis-presence of TDC did not increase the secretory transport of TBuMA in Caco-2 cells, suggesting that the effect of the cis-presence of bile salts on the transport of OCs is hardly observed for Caco-2 cells. Table I summarizes the effect of ion-pair complexation on the secretory transport of berberine and TBuMA across the Caco-2 and LLC-PK1 cell monolayers. The effect of the ion-pair complexation with TDC was observed only for TBuMA in LLC- PK1 cells (Song et al., 2003). Therefore, the effect of ionpair complexation appears to be different depending on the characteristics of OCs (molecular weight, lipophilicity, affinity to relevant transporters, for example) and cell lines (expression and contribution of P-gp and OCTs, for example). For small molecular weight OCs (e.g., triethylmethyl ammonium and tetraethylammonium, Shim et al., 1981; Song et al., 2001) that are not likely to form ion-pair complexes with OAs, the presence of OAs including bile salts may not affect the transcelluar transport of the OCs. In conclusion, the effect of ion-pair complexation on the transcellular transport (e.g., absorption and excretion) of OCs should be considered to be specific to each OC and cell strain. ACKNOWLEDGEMENTS This work was supported by the Korea Science and Engineering Foundation (KOSEF) through the National Research Lab. 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