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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

Infection and Cancer Discovery, AstraZeneca PLC, Waltham, Massachusetts (C.E.G.).; Preclinical Development Drug Metabolism and Pharmacokinetics, AstraZeneca Plc, Wilmington, Delaware (J.L.); Infection and Cancer Discovery, AstraZeneca Plc, Macclesfield, United Kingdom (K.J.); Quest Pharmaceutical Services Inc, Newark, Delaware (E.S., C.-M.L., H.-S.S.); Bristol-Myers Squibb Company, Pennington, New Jersey (G.L., J.D., C.P.D., S.E.M., S.P.); Boehringer Ingelheim Pharmaceuticals, Ridgefield, Connecticut (L.-S.G.); Pharmacokinetics, Pharmacodynamics and Bioanalytical Sciences, Genentech Inc., San Francisco, California (M.Q.); Incyte Pharmaceuticals, Newark, Delaware (T.M.); and Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts (F.W.L.)

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 –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 BA reservoirs exceeded the transport from AB 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 BA 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.