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Metabolic profile of XK469 (2(R)-[4-(7-chloro-2-quinoxalinyl)oxyphenoxy]-propionic acid; NSC698215) in patients and in vitro: low potential for active or toxic metabolites or for drug–drug interactions

Cancer Chemotherapy and Pharmacology volume 56, pages 351–357 (2005)Cite this article

Abstract

As part of an ongoing phase 1 study, we studied the excretion of XK469 and its metabolism in patients and in vitro. Five primary metabolites were identified by HPLC/MS/MS. An oxidized product formed by cytosolic aldehyde oxidase was the predominant species both in urine and human hepatocytes in vitro. Conjugates of XK469 with glycine, taurine, and glucuronic acid, as well as the microsomal product, 4-oxo-XK469, were also found in urine and in vitro, but none were major contributors to the mass balance for XK469 elimination. Based upon the relative concentrations circulating in plasma, systemic exposure to parent drug was 100-fold higher than for the metabolites. Thus, both toxicity and efficacy of XK469 are most likely to be produced by the parent molecule, rather than the metabolites. Urinary recovery of parent drug was low (2% of dose in 24 h), partly because of the long half-life of XK469 (approximately 3 days). In addition, the metabolite profile in urine indicates that only 25% of the XK469-derived material was unchanged drug. Thus, urinary excretion was not a major factor in XK469 elimination. Variations in systemic exposure to XK469 will be strongly influenced by factors that alter the activity of aldehyde oxidase, including pharmacogenetics, enzyme inhibition, and enzyme induction, but no specific modifiers have been reported. The multiday half-life of XK469 hampered our ability to obtain a complete mass balance, and the possibility exists that other routes, such as biliary excretion, may also play a substantial role in XK469 disposition.

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Abbreviations

AO:

Aldehyde oxidase

XK469:

2(R)-[4-(7-Chloro-2-quinoxalinyl)oxyphenoxy]-propionic acid, NSC698215

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Acknowledgements

The authors wish to acknowledge and thank Dr. Jerome P. Horwitz and the staff of his laboratory for their contributions in synthesizing the putative metabolites, and to Dr. Horwitz for his stimulating and thoughtful comments. This work is supported by U01-CA062487.

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Affiliations

  1. Food and Drug Administration, WO Bldg 64, Rm 2014, 10903 New Hampshire Avenue, HFD-902, Silver Spring, MD, 20993

    Lawrence W. Anderson

  2. Laboratory of Clinical Pharmacology, Food and Drug Administration, Silver Spring, MD, USA

    Lawrence W. Anderson, Jerry M. Collins, Raymond W. Klecker & Aspandiar G. Katki

  3. Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA

    Ralph E. Parchment, Ramesh R. Boinpally & Patricia M. LoRusso

  4. Cancer Therapy Evaluation Program, National Cancer Institute, Rockville, MD, USA

    S. Percy Ivy

Authors
  1. Lawrence W. Anderson
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  2. Jerry M. Collins
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  3. Raymond W. Klecker
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  4. Aspandiar G. Katki
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  5. Ralph E. Parchment
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  6. Ramesh R. Boinpally
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  7. Patricia M. LoRusso
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  8. S. Percy Ivy
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Correspondence to Lawrence W. Anderson.

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Anderson, L.W., Collins, J.M., Klecker, R.W. et al. Metabolic profile of XK469 (2(R)-[4-(7-chloro-2-quinoxalinyl)oxyphenoxy]-propionic acid; NSC698215) in patients and in vitro: low potential for active or toxic metabolites or for drug–drug interactions. Cancer Chemother Pharmacol 56, 351–357 (2005). https://doi.org/10.1007/s00280-004-0962-3

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  • DOI: https://doi.org/10.1007/s00280-004-0962-3

Keywords

  • NSC698215
  • Metabolites
  • Drug-drug interactions