title: Role of P-glycoprotein and the intestine in the excretion of DPC 333 [(2R)-2-{(3R)-3-amino-3-[4-(2-methylquinolin-4-ylmethoxy)phenyl]-2-oxopyrrolidin-1-yl}-N-hydroxy-4-methylpentanamide] in rodents.
abstract: 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 alpha-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 [(14)C]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, approximately 20% of an i.v. dose of [(14)C]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.
authors.affiliation: Infection and Cancer Discovery, AstraZeneca PLC, Waltham, Massachusetts 02451, USA. c.edwin.garner@astrazeneca.com
authors.forename: C Edwin
authors.initials: CE
authors.lastname: Garner
authors.forename: Eric
authors.initials: E
authors.lastname: Solon
authors.forename: Chii-Ming
authors.initials: CM
authors.lastname: Lai
authors.forename: Jianrong
authors.initials: J
authors.lastname: Lin
authors.forename: Gang
authors.initials: G
authors.lastname: Luo
authors.forename: Kevin
authors.initials: K
authors.lastname: Jones
authors.forename: Jingwu
authors.initials: J
authors.lastname: Duan
authors.forename: Carl P
authors.initials: CP
authors.lastname: Decicco
authors.forename: Thomas
authors.initials: T
authors.lastname: Maduskuie
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Mercer
authors.forename: Lian-Shen
authors.initials: LS
authors.lastname: Gan
authors.forename: Mingxin
authors.initials: M
authors.lastname: Qian
authors.forename: Shimoga
authors.initials: S
authors.lastname: Prakash
authors.forename: Huey-Shin
authors.initials: HS
authors.lastname: Shen
authors.forename: Frank W
authors.initials: FW
authors.lastname: Lee
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D018938:Caco-2 Cells; D002460:Cell Line; D004285:Dogs; D005260:Female; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D011804:Quinolines / Q000097:blood / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014162:Transfection
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; C476910:BMS561392; D011804:Quinolines