Impact of Mrp2 on the biliary excretion and intestinal absorption of furosemide, probenecid, and methotrexate using Eisai hyperbilirubinemic rats

• Published in: Pharmaceutical research Vol. 20; no. 1; pp. 31 - 37
• Main Authors: CUIPING CHEN, SCOTT, Dennis, HANSON, Elizabeth, FRANCO, Judy, BERRYMAN, Edwin, VOLBERG, Marlo, XINGRONG LIU
• Format: Journal Article
• Language: English
• Published: New York, NY Springer 2003; Springer Nature B.V
• Subjects: Animals; ATP-Binding Cassette Transporters; Biliary Tract - metabolism; Biological and medical sciences; Carrier Proteins - genetics; Carrier Proteins - metabolism; Furosemide - blood; Furosemide - pharmacokinetics; General pharmacology; Hyperbilirubinemia - genetics; Hyperbilirubinemia - metabolism; Intestinal Absorption - physiology; Male; Medical sciences; Methotrexate - blood; Methotrexate - pharmacokinetics; Pharmacokinetics. Pharmacogenetics. Drug-receptor interactions; Pharmacology. Drug treatments; Probenecid - blood; Probenecid - pharmacokinetics; Rats; Rats, Mutant Strains; Rats, Sprague-Dawley; Antineoplastic agent; Sulfanilamide derivatives; Eisai hyperbilirubinemic rats; Intravenous administration; Rat; Uricosuric agent; Blood plasma; Absorption; Hyperbilirubinemia; biliary excretion; Multiple resistance; Methotrexate; Probenecid; Excretion; Sulfonamide; multidrug resistance-associated protein 2; Digestive system; Rodentia; Gut; Furosemide; Vertebrata; Mammalia; Animal; Antihypertensive agent; Pharmacokinetics; Bile
• ISSN: 0724-8741; 1573-904X
• DOI: 10.1023/a:1022238506509

This study assesses the impact of rat multidrug resistance-associated protein 2 (Mrp2) on the biliary excretion and oral absorption of furosemide, probenecid, and methotrexate using Eisai hyperbilirubinemic rats (EHBR).
To assess Mrp2-mediated biliary excretion, rats received a 2-h intravenous infusion of furosemide, probenecid, or methotrexate. Blood and bile samples were collected at specified intervals. To assess Mrp2's impact on oral absorption, rats received furosemide, probenecid, or methotrexate orally at 5 mg/kg. Jugular and portal blood samples were obtained at timed intervals. All samples were analyzed by LC-MS/MS. Pharmacokinetic parameters were estimated using WinNonlin and standard pharmacokinetic equations.
Thirty seven- and 39-fold reductions in biliary clearance were observed in EHBR as compared to control rats for probenecid and methotrexate, respectively. Biliary clearance was comparable between EHBR and control rats for furosemide. In all cases, no significant difference in absorption was observed between EHBR and control rats.
This study provides the first evidence that Mrp2 mediates the biliary excretion of probenecid but not furosemide. Additionally, Mrp2 apparently has a less profound impact on intestinal absorption than biliary excretion of its substrates. Furthermore, alteration in systemic clearance in EHBR indicates that a potential compensatory mechanism may occur in EHBR.