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

Maeng, Han‐Joo; Yoo, Ho-Jung; Kim, In‐Wha; Song, Im‐Sook; Chung, Suk‐Jae; Shim, Chang‐Koo

doi:10.1002/jps.10268

Cited by 105 publications

(75 citation statements)

References 30 publications

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“…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.…”

Section: Transport Of Berberine In Caco-2 Cell Monolayerscontrasting

confidence: 74%

“…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).…”

Section: Transport Studymentioning

confidence: 99%

“…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).…”

Section: Effect Of the Bile And Tdc On The Transport Of Berberine Acrmentioning

confidence: 99%

“…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).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2008

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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).

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Section: Transport Of Berberine In Caco-2 Cell Monolayerscontrasting

confidence: 74%

Section: Transport Studymentioning

confidence: 99%

Section: Effect Of the Bile And Tdc On The Transport Of Berberine Acrmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2008

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“…Often combined with echinacea, goldenseal-containing supplements currently rank among the top-selling botanicals in the United States. Recent in vitro studies have shown that an isoquinoline alkaloid present in goldenseal, berberine, is a substrate for P-gp (Maeng et al, 2002;Pan et al, 2002;Tsai and Tsai, 2004) that exhibits disparate modulatory effects on P-gp-mediated drug efflux (Lin et al, 1999a,b;Tsai et al, 2001;Efferth et al, 2002;He and Liu, 2002;Maeng et al, 2002). Kava kava has long been a traditional beverage consumed among South Pacific islanders to imbue psychotropic, hypnotic, and anxiolytic effects (Ulbricht et al, 2005).…”

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confidence: 99%

Effect of Goldenseal (Hydrastis canadensis) and Kava Kava (Piper methysticum) Supplementation on Digoxin Pharmacokinetics in Humans

et al. 2006

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ABSTRACT:Phytochemical-mediated modulation of P-glycoprotein (P-gp) and other drug transporters may give rise to many herb-drug interactions. Serial plasma concentration-time profiles of the P-gp substrate, digoxin, were used to determine whether supplementation with goldenseal or kava kava modified P-gp activity in vivo. Twenty healthy volunteers were randomly assigned to receive a standardized goldenseal (3210 mg daily) or kava kava (1227 mg daily) supplement for 14 days, followed by a 30-day washout period. Subjects were also randomized to receive rifampin (600 mg daily, 7 days) and clarithromycin (1000 mg daily, 7 days) as positive controls for P-gp induction and inhibition, respectively. Digoxin (Lanoxin, 0.5 mg) was administered p.o. before and at the end of each supplementation and control period. Serial digoxin plasma concentrations were obtained over 24 h and analyzed by chemiluminescent immunoassay. Comparisons of area under the curve (AUC) (0-3) , AUC (0-24) , C max, CL/F, and elimination half-life were used to assess the effects of goldenseal, kava kava, rifampin, and clarithromycin on digoxin pharmacokinetics. Rifampin produced significant reductions (p < 0.01) in AUC (0-3) , AUC (0-24) , CL/F, t 1/2 , and C max , whereas clarithromycin increased these parameters significantly (p < 0.01). With the exception of goldenseal's effect on C max (14% increase), no statistically significant effects on digoxin pharmacokinetics were observed following supplementation with either goldenseal or kava kava. When compared with rifampin and clarithromycin, supplementation with these specific formulations of goldenseal or kava kava did not appear to affect digoxin pharmacokinetics, suggesting that these supplements are not potent modulators of P-gp in vivo.

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Assessing Transporter‐Mediated Natural Product‐Drug Interactions Via In vitro‐In Vivo Extrapolation: Clinical Evaluation With a Probe Cocktail

Nguyen

Tian

Tanna

et al. 2020

Clin Pharma and Therapeutics

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The botanical natural product goldenseal can precipitate clinical drug interactions by inhibiting cytochrome P450 (CYP) 3A and CYP2D6. Besides P‐glycoprotein, effects of goldenseal on other clinically relevant transporters remain unknown. Established transporter‐expressing cell systems were used to determine the inhibitory effects of a goldenseal extract, standardized to the major alkaloid berberine, on transporter activity. Using recommended basic models, the extract was predicted to inhibit the efflux transporter BCRP and uptake transporters OATP1B1/3. Using a cocktail approach, effects of the goldenseal product on BCRP, OATP1B1/3, OATs, OCTs, MATEs, and CYP3A were next evaluated in 16 healthy volunteers. As expected, goldenseal increased the area under the plasma concentration‐time curve (AUC0–inf) of midazolam (CYP3A; positive control), with a geometric mean ratio (GMR) (90% confidence interval (CI)) of 1.43 (1.35–1.53). However, goldenseal had no effects on the pharmacokinetics of rosuvastatin (BCRP and OATP1B1/3) and furosemide (OAT1/3); decreased metformin (OCT1/2, MATE1/2‐K) AUC0–inf (GMR, 0.77 (0.71–0.83)); and had no effect on metformin half‐life and renal clearance. Results indicated that goldenseal altered intestinal permeability, transport, and/or other processes involved in metformin absorption, which may have unfavorable effects on glucose control. Inconsistencies between model predictions and pharmacokinetic outcomes prompt further refinement of current basic models to include differential transporter expression in relevant organs and intestinal degradation/metabolism of the precipitant(s). Such refinement should improve in vitro‐in vivo prediction accuracy, contributing to a standard approach for studying transporter‐mediated natural product‐drug interactions.

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

Cited by 105 publications

References 30 publications

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

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

Effect of Goldenseal (Hydrastis canadensis) and Kava Kava (Piper methysticum) Supplementation on Digoxin Pharmacokinetics in Humans

Assessing Transporter‐Mediated Natural Product‐Drug Interactions Via In vitro‐In Vivo Extrapolation: Clinical Evaluation With a Probe Cocktail

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