Metabolism of UCN-01 in isolated perfused rat liver: role of Mrp2 in the biliary excretion of glucuronides

Oncol Rep. 2004 May;11(5):1069-75. doi: 10.3892/or.11.5.1069.


UCN-01 is a promising, novel kinase inhibitor currently undergoing clinical development. Though UCN-01 shows pronounced antitumor activity, its metabolism and hepatic transport system is still unknown. To investigate the biotransformation and biliary excretion of UCN-01, livers of Wistar and Mrp2-deficient TR- rats were perfused with UCN-01 (0.2 microM) in a single pass system. In bile and perfusate, native UCN-01 and 5 novel metabolites (M1-M5) were quantified by HPLC and identified as glucuronides by enzymatic hydrolysis with beta-glucuronidase and mass spectroscopy. Cumulative efflux of UCN-01 and its metabolites M1-M5 into perfusate of Wistar rats was low (<0.14%) whereas total biliary excretion was up to 53-fold higher, representing 1.74, 0.54, 0.21, 1.17, 0.85 and 0.52% of infused UCN-01, respectively. After 60 min of perfusion, liver cells still contained approximately 95% of applied UCN-01. Biliary excretion greatly differs in TR- rats. While cumulative biliary excretion of UCN-01 and its metabolites M1-M5 was significantly reduced to 8.3, 5.3, 31.8, 10.4, 13.2 and 7.8%, efflux into perfusate was increased up to 2.2-fold. This indicates that in control rats, UCN-01 and its glucuronides are almost exclusively eliminated into bile by Mrp2. In summary, UCN-01 is extensively metabolized in the rat liver to 5 novel glucuronides mainly excreted into bile by Mrp2. Metabolism and biliary excretion of UCN-01 must be taken into consideration also during cancer therapy of patients.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP-Binding Cassette Transporters / metabolism*
  • Animals
  • Antineoplastic Agents / metabolism*
  • Antineoplastic Agents / pharmacokinetics
  • Bile / metabolism*
  • Biological Availability
  • Glucuronides / metabolism*
  • Kinetics
  • Liver / drug effects
  • Liver / metabolism*
  • Perfusion
  • Rats
  • Rats, Mutant Strains
  • Rats, Wistar
  • Staurosporine / analogs & derivatives*
  • Staurosporine / metabolism*
  • Staurosporine / pharmacokinetics


  • ATP-Binding Cassette Transporters
  • Abcc2 protein, rat
  • Antineoplastic Agents
  • Glucuronides
  • 7-hydroxystaurosporine
  • Staurosporine