PPAR Research 
Volume 2008 (2008), Article ID 465715, 10 pages
doi:10.1155/2008/465715
Research Article

Cross-Species Differential Plasma Protein Binding of MBX-102/JNJ39659100: A Novel PPAR-γ Agonist

Holly J. Clarke,1,2 Francine Gregoire,1 Fang Ma,1 Robert Martin,1 Spring Zhao,1 and Brian E. Lavan1

 1Research and Preclinical Development, Metabolex, Inc., 3876 Bay Center Place, Hayward, CA 94545, USA
2Department of Molecular Biology, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA
Received 25 March 2008; Accepted 15 July 2008

Recommended by Anne Miller

Abstract

Drug binding to plasma proteins restricts their free and active concentrations, thereby affecting their pharmacokinetic properties. Species differences in plasma protein levels complicate the understanding of interspecies pharmacodynamic and toxicological effects. MBX-102 acid/JNJ39659100 is a novel PPAR-γ agonist in development for the treatment of type 2 diabetes. Studies were performed to evaluate plasma protein binding to MBX-102 acid and evaluate species differences in free drug levels. Equilibrium dialysis studies demonstrated that MBX-102 acid is highly bound (>98%) to human, rat and mouse albumin and that free MBX-102 acid levels are higher in rodent than in human plasma. Interspecies differences in free drug levels were further studied using PPAR-γ transactivation assays and a newly developed PPAR-γ corepressor displacement (biochemical) assay. PPAR-γ transactivation and corepressor displacement by MBX-102 acid was higher in rat and mouse serum than human serum. These results confirm the relevance of interspecies differences in free MBX-102 acid levels.