RT Journal Article
SR Electronic
T1 Pharmacokinetics and Pharmacodynamics of DPC 333 ((2R)-2-((3R)-3-Amino-3{4-[2-methyl-4-quinolinyl) methoxy] phenyl}-2-oxopyrrolidinyl)-N-hydroxy-4-methylpentanamide)), a Potent and Selective Inhibitor of Tumor Necrosis Factor α-Converting Enzyme in Rodents, Dogs, Chimpanzees, and Humans
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 1916
OP 1925
DO 10.1124/dmd.107.015933
VO 35
IS 10
A1 Mingxin Qian
A1 Stephen A. Bai
A1 Bernice Brogdon
A1 Jing-Tao Wu
A1 Rui-Qin Liu
A1 Maryanne B. Covington
A1 Kris Vaddi
A1 Robert C. Newton
A1 Michael J. Fossler
A1 C. Edwin Garner
A1 Yuzhong Deng
A1 Thomas Maduskuie
A1 James Trzaskos
A1 James J.-W. Duan
A1 Carl P. Decicco
A1 David D. Christ
YR 2007
UL http://dmd.aspetjournals.org/content/35/10/1916.abstract
AB DPC 333 ((2R)-2-((3R)-3-amino-3{4-[2-methyl-4-quinolinyl) methoxy] phenyl}-2-oxopyrrolidinyl)-N-hydroxy-4-methylpentanamide)) is a potent and selective inhibitor of tumor necrosis factor (TNF)-α-converting enzyme (TACE). It significantly inhibits lipopolysaccharide-induced soluble TNF-α production in blood from rodents, chimpanzee, and human, with IC50 values ranging from 17 to 100 nM. In rodent models of endotoxemia, DPC 333 inhibited the production of TNF-α in a dose-dependent manner, with an oral ED50 ranging from 1.1 to 6.1 mg/kg. Oral dosing of DPC 333 at 5.5 mg/kg daily for 2 weeks in a rat collagen antibody-induced arthritis model suppressed the maximal response by approximately 50%. DPC 333 was distributed widely to tissues including the synovium, the site of action for antiarthritic drugs. Pharmacokinetic and pharmacodynamic studies in chimpanzee revealed a systemic clearance of 0.4 l/h/kg, a Vss of 0.6 l/kg, an oral bioavailability of 17%, and an ex vivo IC50 for the suppression of TNF-α production of 55 nM (n = 1). In a phase I clinical trial with male volunteers after single escalating doses of oral DPC 333, the terminal half-life was between 3 and 6 h and the ex vivo IC50 for suppressing TNF-α production was 113 nM. Measurement of the suppression of TNF-α production ex vivo may serve as a good biomarker in evaluating the therapeutic efficacy of TACE inhibitors. Overall, the pharmacological profiles of DPC 333 support the notion that suppression of TNF-α with TACE inhibitors like DPC 333 may provide a novel approach in the treatment of various inflammatory diseases including rheumatoid arthritis, via control of excessive TNF-α production. The American Society for Pharmacology and Experimental Therapeutics