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