TY - JOUR T1 - Role of P-Glycoprotein and the Intestine in the Excretion of DPC 333 [(2<em>R</em>)-2-{(3<em>R</em>)-3-Amino-3-[4-(2-methylquinolin-4-ylmethoxy)phenyl]-2-oxopyrrolidin-1-yl}-<em>N</em>-hydroxy-4-methylpentanamide] in Rodents JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 1102 LP - 1110 DO - 10.1124/dmd.107.017038 VL - 36 IS - 6 AU - C. Edwin Garner AU - Eric Solon AU - Chii-Ming Lai AU - Jianrong Lin AU - Gang Luo AU - Kevin Jones AU - Jingwu Duan AU - Carl P. Decicco AU - Thomas Maduskuie AU - Stephen E. Mercer AU - Lian-Shen Gan AU - Mingxin Qian AU - Shimoga Prakash AU - Huey-Shin Shen AU - Frank W. Lee Y1 - 2008/06/01 UR - http://dmd.aspetjournals.org/content/36/6/1102.abstract N2 - The role of the intestine in the elimination of (2R)-2-{(3R)-3-amino-3-[4-(2-methylquinolin-4-ylmethoxy)phenyl]-2-oxopyrrolidin-1-yl}-N-hydroxy-4-methylpentanamide (DPC 333), a potent inhibitor of tissue necrosis factor α–converting enzyme, was investigated in mice and rats in vivo and in vitro. In Madine-Darby canine kidney cells stably transfected with P-glycoprotein (P-gp) and DPC 333, the transport from B→A reservoirs exceeded the transport from A→B by approximately 7-fold. In Caco-2 monolayers and isolated rat ileal mucosa, DPC 333 was transported from basolateral to apical reservoirs in a concentration-dependent, saturable manner, and transport was blocked by N-(4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)ethyl]-phenyl)-9,10-dihydro-5-methoxy-9-oxo-4-acridine carboxamide (GF120918), confirming the contribution of P-gp/breast cancer resistance protein in B→A efflux of DPC 333. In quantitative whole body autoradiography studies with [14C]DPC 333 in mice and rats, radioactivity was distributed throughout the small intestine in both species. In GF120918-pretreated bile duct–cannulated rats, radioactivity in feces was reduced 60%. Using the in situ perfused rat intestine model, ∼20% of an i.v. dose of [14C]DPC 333 was measured in the intestinal lumen within 3 h postdose, 12% as parent. Kinetic analysis of data suggested that excreted DPC 333 may be further metabolized in the gut. Intestinal clearance was 0.2 to 0.35 l/h/kg. The above data suggest that in the rodent the intestine serves as an organ of DPC 333 excretion, mediated in part by the transporter P-gp. The American Society for Pharmacology and Experimental Therapeutics ER -