Biliary excretion of curcumin is mediated by multidrug resistance-associated protein 2.
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.
Division of Biopharmaceutics, College of Pharmacy, Kyung Hee University, Seoul, Korea.
Joo Hyun
JH
Lee
Ju-Hee
JH
Oh
Young-Joo
YJ
Lee
D000818:Animals; D001646:Bile / Q000378:metabolism*; D001650:Bile Duct Neoplasms / Q000188:drug therapy / Q000378:metabolism; D001653:Bile Ducts, Intrahepatic; D001659:Biliary Tract / Q000378:metabolism*; D018281:Cholangiocarcinoma / Q000188:drug therapy / Q000378:metabolism; D030024:Curcuma / Q000737:chemistry; D003474:Curcumin / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D006932:Hyperbilirubinemia / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism*; D008517:Phytotherapy; D010936:Plant Extracts / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D010949:Plasma / Q000378:metabolism; D011110:Polymorphism, Genetic; D051381:Rats; D017207:Rats, Sprague-Dawley
D003474:Curcumin; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D010936:Plant Extracts