Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
2486247 | Journal of Pharmaceutical Sciences | 2010 | 12 Pages |
Abstract
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 (180âµg) 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 (0-90âmin) perfusate and bile and terminal liver samples were collected for analysis by HPLC. In the Control livers, 25.4â±â2.2% (meanâ±âSD) of the dose was recovered as RH-123 (11.7â±â2.0%) and RH-Glu (13.2â±â0.9%) in the bile. Whereas CyA substantially (90%) reduced (pâ<â0.001) the biliary excretion of RH-123 without affecting the excretion of RH-Glu, DBSP reduced the biliary excretion of RH-Glu by >80% (pâ<â0.001) 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. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:455-466, 2010
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Authors
Ridhi Parasrampuria, Reza Mehvar,