Effects of P-glycoprotein and Mrp2 inhibitors on the hepatobiliary disposition of Rhodamine 123 and its glucuronidated metabolite in isolated perfused rat livers

✍ Scribed by Ridhi Parasrampuria; Reza Mehvar

• Publisher: John Wiley and Sons
• Year: 2010
• Tongue: English
• Weight: 300 KB
• Volume: 99
• Category: Article
• ISSN: 0022-3549
• DOI: 10.1002/jps.21831

✦ Synopsis

The hepatobiliary disposition of rhodamine 123 (RH-123) and its glucuronidated (RH-Glu) and deacylated (RH-110) metabolites were studied in an isolated perfused rat liver (IPRL) model in the presence and absence of P-glycoprotein (P-gp) and Mrp2 inhibitors. A single dose (180 mg) of RH-123 was added to a recirculating perfusate in the absence (Control) or presence of cyclosporine A (CyA) or dibromosulfophthalein (DBSP) in the perfusate. Serial (0-90 min) perfusate and bile and terminal liver samples were collected for analysis by HPLC. In the Control livers, 25.4 AE 2.2% (mean AE SD) of the dose was recovered as RH-123 (11.7 AE 2.0%) and RH-Glu (13.2 AE 0.9%) in the bile. Whereas CyA substantially (90%) reduced ( p < 0.001) the biliary excretion of RH-123 without affecting the excretion of RH-Glu, DBSP reduced the biliary excretion of RH-Glu by >80% ( p < 0.001) with no effect on the biliary excretion of RH-123. Mass balance studies showed that DBSP, in addition to reducing the biliary clearance of RH-Glu, also strongly inhibited the glucuronidation of RH-123, an effect that was confirmed in vitro using the glucuronidation marker umbelliferone. It is concluded that the use of RH-123 in an IPRL model may serve as a dual marker for the determination of the altered functions of P-gp and/or Mrp2.