Biliary Excretion of Curcumin Is Mediated by Multidrug Resistance-Associated Protein 2

Abstract

Curcumin has a wide spectrum of pharmacological activities, including antioxidant, anti-inflammatory, antimicrobial, and anticancer properties. Recently, its potential as effective chemoprevention against cholangiocarcinoma, a highly malignant tumor of the bile duct with limited therapeutic options, was reported. The purpose of the present study was to investigate the contribution of multidrug resistance-associated protein 2 (Mrp2) to the biliary excretion of curcumin using Sprague-Dawley rats (SDR) and Eisai hyperbilirubinemic rats (EHBR). After intravenous administration of curcumin with a loading dose of 4.5 mg/kg, followed by a constant infusion of 18 mg/kg/h to the SDR and EHBR, the pharmacokinetic parameters of curcumin were estimated. In EHBR, the total area under the bile concentration-time curve from 0 to 80 min following curcumin administration was dramatically decreased (0.094%) compared to that in SDR. In addition, the plasma-to-bile and liver-to-bile clearances were both significantly decreased compared to SDR. These results provide the first evidence that Mrp2 mediates the biliary excretion of curcumin and thus may be a major factor in the control of exposure of curcumin to the bile duct. This study may be helpful to the potential use of curcumin as a treatment for bile duct cancer, and to understanding the genetic polymorphism of Mrp2 for clinical trials of curcumin.

Dramatic increase in hepatic and biliary curcumin exposure by modulation of its elimination pathway in rats

“…The increased biliary excretion of curcumin by probenecid despite the decreased liver‐to‐bile clearance may have been attributed to the large increase in the hepatic curcumin concentration. Similar results were reported in a previous study in which the AUC 0–80 min and total body clearance of curcumin were not significantly changed in an Mrp2‐defecient rat, despite the significantly reduced biliary excretion, suggesting limited contribution of biliary excretion toward the elimination of curcumin …”

“…Curcumin dissolved in solution A : B = 2 : 1 was intravenously administered to rats at an infusion rate of 18 mg/kg/h, either without ( n = 4) or with ( n = 4) probenecid at a rate of 230 mg/kg/h for over 80 min. Just before the infusion, 4.5 mg/kg curcumin either without or with 100 mg/kg probenecid dissolved in solution A : B = 1 : 1 was administered as a loading dose . Plasma and bile samples were collected at 0, 20, 40, 60, and 80 min after starting the infusion, and were stored at −80°C for subsequent use in HPLC analysis.…”

“…Just before the infusion, 4.5 mg/kg curcumin either without or with 100 mg/kg probenecid dissolved in solution A : B = 1 : 1 was administered as a loading dose. [21] Plasma and bile samples were collected at 0, 20, 40, 60, and 80 min after starting the infusion, and were stored at -80°C for subsequent use in HPLC analysis. After the infusion was stopped, the brain, liver, kidney, and small intestine of each rat were removed, homogenized in 2 ¥ phosphate-buffered saline by using a T10 basic Ultra-Turrax Homogenizer (IKA IKA Works, Inc., SP, Brazil), and stored at -80°C until analysis.…”

“…However, the effect that these metabolic inhibitors have on the concentration of curcumin in target organs such as the liver is still unclear. Curcumin in the liver is rapidly excreted into bile by the multidrug resistance‐associated protein 2 (Mrp2), and so the liver concentration of curcumin is lower than its plasma concentration and remains a critical marker for the therapeutic use of curcumin for liver disease …”

“…Curcumin in the liver is rapidly excreted into bile by the multidrug resistanceassociated protein 2 (Mrp2), and so the liver concentration of curcumin is lower than its plasma concentration and remains a critical marker for the therapeutic use of curcumin for liver disease. [21] We have used probenecid, a uricosuric drug, as a modulator for enhancing the hepatic availability of curcumin. Probenecid inhibits glucuronidation of drugs via uridine diphosphate glucuronosyltransferase in a dose-dependent manner, and inhibits the biliary excretion of anionic compounds via Mrp2.…”