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Drug Metabolism and Disposition Fast Forward
First published on July 28, 2004; DOI: 10.1124/dmd.104.000323

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Received for publication April 21, 2004.
Revised July 26, 2004.
Accepted for publication July 27, 2004.

TISSUE DISTRIBUTION, STABILITY AND PHARMACOKINETICS OF APO2L/TRAIL IN COLO205 TUMOR-BEARING NUDE MICE

Hong Xiang 1, Cindy B Nguyen 1, Sean K Kelley 1, Noel Dybdal 1, Enrique Escandon 1*

1 Genentech, Inc.

* Address correspondence to: E-mail: enrique904{at}hotmail.com

Abstract

Apo2L/TRAIL, a member of the TNF cytokine superfamily, induces cell death by apoptosis in a number of human cancer cells and is a potential agent for cancer therapy. We have characterized the in vitro stability of Apo2L/TRAIL in human serum and the tissue distribution and metabolism of Apo2L/TRAIL in a xenograft model of human colon carcinoma (COLO205). Apo2L/TRAIL was stable following incubation in human serum with no significant high molecular weight complexes or degradation products observed. Following IV administration of 125I-Apo2L/TRAIL to mice, a small percent of the radiolabeled drug was seen as high molecular weight complex or as low molecular weight degradation products in plasma. However, the most abundant radioactive species corresponded to the intact Apo2L/TRAIL monomer indicative of the relative stability of this recombinant protein in blood. Distribution of 125I Apo2L/TRAIL to organs and solid xenograft tumors was limited. Intact 125I Apo2L/TRAIL was detectable in the solid tumor at all timepoints and was the only tissue where radioactivity transiently increased over time. Kidney contained the highest levels of radioactivity. Radioactive signal reached a tissue to blood ratio of 18 in the kidney cortex region when 125I Apo2L/TRAIL was given in the presence of excess unlabeled ligand. In contrast to blood, extensive 125I Apo2L/TRAIL degradation was observed in the kidney and, to a lesser degree, in the solid tumor and other organs including liver, spleen and lung. Our studies demonstrated that Apo2L/TRAIL is stable in the circulation, localizes to human solid xenograft tumors and primarily eliminated through the kidney.


Key words: anticancer agents, drug distribution, pharmacokinetics


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