RT Journal Article
SR Electronic
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
FD American Society for Pharmacology and Experimental Therapeutics
SP 1102
OP 1110
DO 10.1124/dmd.107.017038
VO 36
IS 6
A1 Garner, C. Edwin
A1 Solon, Eric
A1 Lai, Chii-Ming
A1 Lin, Jianrong
A1 Luo, Gang
A1 Jones, Kevin
A1 Duan, Jingwu
A1 Decicco, Carl P.
A1 Maduskuie, Thomas
A1 Mercer, Stephen E.
A1 Gan, Lian-Shen
A1 Qian, Mingxin
A1 Prakash, Shimoga
A1 Shen, Huey-Shin
A1 Lee, Frank W.
YR 2008
UL http://dmd.aspetjournals.org/content/36/6/1102.abstract
AB 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