Abstract
ZD6474 [N-(4-bromo-2-fluorophenyl)-6-methoxy-7-[(1-methylpiperidin-4-yl)methoxy]-quinazolin-4-amine; Zactima] is a tyrosine kinase inhibitor with antiangiogenic and antitumor activity currently undergoing human trials for cancer treatment. Pharmacokinetic studies in animal models are an important component in the clinical development of this agent to relate preclinical studies to patient treatment. In the studies presented here, the pharmacokinetics of ZD6474 was determined in plasma and tissues of MCF-7 tumor-bearing nude mice following single p.o. doses at 10, 25, and 50 mg/kg. Plasma area under the curve and Cmax were linear, increasing proportionally with dose. Tissue analysis showed that ZD6474 is extensively distributed to tissues, with liver and lung accumulating concentrations of 212 μg/g (∼450 μM) and 161 μg/g (∼340 μM), respectively. Tumor levels ranged from 27 to 71 μg/g at Cmax levels across the three dose ranges, and ZD6474 was distributed to all of the tissues in a dose-dependent manner. Analysis of putative ZD6474 metabolites in feces found four, with the N-demethyl-piperidinyl-ZD6474 metabolite being the most prominent but still accounting for less than 2% of the total amount of ZD6474 present. The lack of significant metabolism of ZD6474 is consistent with the relatively long half-life in mice (∼30 h), as well as that seen in humans (∼120 h), and the primary method of drug elimination appears to be unchanged in the feces (∼25%). The incorporation of an empirical approach to dosing in mouse models of cancer in preclinical studies may allow for better prediction of clinical efficacy for ZD6474 alone and in combination with other therapeutic modalities based on equivalent drug exposure.
Footnotes
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This work was supported by Grant CA101988 from the National Cancer Institute (D.L.G.).
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.106.102376.
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ABBREVIATIONS: RTK, receptor tyrosine kinase(s); ZD6474, N-(4-bromo-2-fluorophenyl)-6-methoxy-7-[(1-methylpiperidin-4-yl)methoxy]-quinazolin-4-amine; MRM, multiple reaction monitoring; CID, collision-induced dissociation; AUC, area under the curve.
- Received February 2, 2006.
- Accepted April 24, 2006.
- The American Society for Pharmacology and Experimental Therapeutics
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