title: Disposition of [14C]ruboxistaurin in humans.
abstract: Ruboxistaurin is a potent and specific inhibitor of the beta isoforms of protein kinase C (PKC) that is being developed for the treatment of diabetic microvascular complications. The disposition of [(14)C]ruboxistaurin was determined in six healthy male subjects who received a single oral dose of 64 mg of [(14)C]ruboxistaurin in solution. There were no clinically significant adverse events during the study. Whole blood, urine, and feces were collected at frequent intervals after dosing. Metabolites were profiled by high performance liquid chromatography with radiometric detection. The total mean recovery of the radioactive dose was approximately 87%, with the majority of the radioactivity (82.6 +/- 1.1%) recovered in the feces. Urine was a minor pathway of elimination (4.1 +/- 0.3%). The major route of ruboxistaurin metabolism was to the N-desmethyl ruboxistaurin metabolite (LY338522), which has been shown to be active and equipotent to ruboxistaurin in the inhibition of PKC(beta). In addition, multiple hydroxylated metabolites were identified by liquid chromatography-mass spectrometry in all matrices. Pharmacokinetics were conducted for both ruboxistaurin and LY338522 (N-desmethyl ruboxistaurin, 1). These moieties together accounted for approximately 52% of the radiocarbon measured in the plasma. The excreted radioactivity was profiled using radiochromatography, and approximately 31% was structurally characterized as ruboxistaurin or N-desmethyl ruboxistaurin. These data demonstrate that ruboxistaurin is metabolized primarily to N-desmethyl ruboxistaurin (1) and multiple other oxidation products, and is excreted primarily in the feces.
authors.affiliation: Lilly Research Laboratories, A Division of Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA. Burkey_jennifer_l@lilly.com
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Burkey
authors.forename: Kristina M
authors.initials: KM
authors.lastname: Campanale
authors.forename: Robert
authors.initials: R
authors.lastname: Barbuch
authors.forename: Douglas
authors.initials: D
authors.lastname: O'Bannon
authors.forename: James
authors.initials: J
authors.lastname: Rash
authors.forename: Charles
authors.initials: C
authors.lastname: Benson
authors.forename: David
authors.initials: D
authors.lastname: Small
mesh_terms: D000284:Administration, Oral; D000328:Adult; D002250:Carbon Radioisotopes; D002853:Chromatography, Liquid; D004791:Enzyme Inhibitors / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D005243:Feces / Q000737:chemistry; D006801:Humans; D007211:Indoles / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics* / Q000652:urine; D008297:Male; D008301:Maleimides / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics* / Q000652:urine; D008875:Middle Aged; D015394:Molecular Structure; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D064546:Protein Kinase C beta; D053719:Tandem Mass Spectrometry; D014018:Tissue Distribution
chemical_list: D002250:Carbon Radioisotopes; D004791:Enzyme Inhibitors; D007211:Indoles; C474461:LY 338522; D008301:Maleimides; C099154:ruboxistaurin; D011493:Protein Kinase C; D064546:Protein Kinase C beta