title: Metabolism of UCN-01 in isolated perfused rat liver: role of Mrp2 in the biliary excretion of glucuronides.
abstract: 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.
authors.affiliation: Institute of Pharmaceutical Chemistry, University of Vienna, A-1090 Vienna, Austria.
authors.forename: Birgit
authors.initials: B
authors.lastname: Hagenauer
authors.forename: Alexandra
authors.initials: A
authors.lastname: Maier-Salamon
authors.forename: Theresia
authors.initials: T
authors.lastname: Thalhammer
authors.forename: Peter
authors.initials: P
authors.lastname: Zöllner
authors.forename: Adrian
authors.initials: A
authors.lastname: Senderowicz
authors.forename: Walter
authors.initials: W
authors.lastname: Jäger
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism* / Q000493:pharmacokinetics; D001646:Bile / Q000378:metabolism*; D001682:Biological Availability; D020719:Glucuronides / Q000378:metabolism*; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D010477:Perfusion; D051381:Rats; D011922:Rats, Mutant Strains; D017208:Rats, Wistar; D019311:Staurosporine / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000493:pharmacokinetics
chemical_list: D018528:ATP-Binding Cassette Transporters; C423013:Abcc2 protein, rat; D000970:Antineoplastic Agents; D020719:Glucuronides; C054852:7-hydroxystaurosporine; D019311:Staurosporine