DMD Simcyp

Home Help [Feedback] [For Subscribers] [Archive] [Search] --
QUICK SEARCH:   [advanced]


     

Drug Metabolism and Disposition Fast Forward
First published on August 8, 2006; DOI: 10.1124/dmd.106.009894

This Article
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
dmd.106.009894v1
34/11/1909    most recent
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Burkey, J. L.
Right arrow Articles by Small, D.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Burkey, J. L.
Right arrow Articles by Small, D.


Received for publication February 22, 2006.
Revised August 2, 2006.
Accepted for publication August 2, 2006.

Disposition of [14C] Ruboxistaurin in Humans

Jennifer L. Burkey 1*, Kristina M Campanale 1, Robert Barbuch 1, Douglas O'bannon 1, James T Rash 1, Charles Benson 2, David Small 1

1 Eli Lilly and Company, Lilly Corporate Center 2 Eli Lilly and Company,Erl Wood ELCL, United Kingdom of Great Britain and Northern Ireland

* Address correspondence to: E-mail: burkey_jennifer_l{at}lilly.com

Abstract

Ruboxistaurin is a potent and specific inhibitor of the {beta} isoforms of Protein Kinase C (PKC) which is being developed for the treatment of diabetic microvascular complications. The disposition of [14C]ruboxistaurin was determined in six healthy male subjects who received a single oral dose of 64 mg [14C]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 (HPLC) 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 LC/MS 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.


Key words: drug disposition, excretion, human pharmacokinetics, metabolite identification


This article has been cited by other articles:


Home page
 Drug Metab. Dispos.Home page
L. Xu, B. Adams, V. V. Jeliazkova-Mecheva, L. Trimble, G. Kwei, and A. Harsch
Identification of Novel Metabolites of Colchicine in Rat Bile Facilitated by Enhanced Online Radiometric Detection
Drug Metab. Dispos., April 1, 2008; 36(4): 731 - 739.
[Abstract] [Full Text] [PDF]


Home Help [Feedback] [For Subscribers] [Archive] [Search] --
All ASPET Journals Molecular Pharmacology Pharmacological Reviews
Molecular Interventions Drug Metabolism and Disposition

Copyright © 2006 by the American Society for Pharmacology and Experimental Therapeutics.