Received for publication July 9, 2007.
Revised March 12, 2008.
Accepted for publication March 13, 2008.

Role of Intestinal P-Glycoprotein 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 DPC 333, [(2R)-2-{(3R)-3-Amino-3-[4-(2-methylquinolin-4-ylmethoxy)phenyl]-2-oxopyrrolidin-1-yl}-N-hydroxy-4-methylpentanamide] a potent inhibitor of tissue necrosis factor alpha converting enzyme, was investigated in mice and rats in vivo and in vitro. In MDCK cells stably transfected with p-glycoprotein (P-gp), DPC 333 the transport from B to A reservoirs exceeded the transport from A to B by ca 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 GF120918, confirming the contribution of P-gp/BCRP in B to A efflux of DPC 333. In QWBA studies with [¹⁴C]-DPC 333 in mice and rats radioactivity was distributed throughout the small intestine in both species. In GF120918 pretreated bile cannulated rats radioactivity in feces was reduced 60%. Using the in situ perfused rat intestine model, ~20% of an IV dose of [¹⁴C]-DPC 333 was measured in the intestinal lumen within 3h post dose; 12% as parent. Kinetic analysis of data suggested that excreted DPC 333 may be further metabolized in the gut. Intestinal clearance was 0.2-0.35 l/hr/kg. The above data suggests that, in the rodent, the intestine serves as an organ of DPC 333 excretion, mediated in part by the transporter p-glycoprotein.

Key words: ABC transporters, drug clearance, drug disposition, drug distribution, drug efflux, drug secretion, intestinal transport, p-glycoprotein, pharmacokinetics, transporters

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