Single-dose pharmacokinetic and toxicity analysis of pyrrole-imidazole polyamides in mice

Timothy W. Synold, Bixin Xi, Jun Wu, Yun Yen, Benjamin C. Li, Fei Yang, John W. Phillips, Nicholas G. Nickols, Peter B. Dervan

研究成果: 雜誌貢獻文章同行評審

28 引文 斯高帕斯(Scopus)

摘要

Purpose Pyrrole-imidazole (Py-Im) polyamides are programmable, sequence-specific DNA minor groove-binding ligands. Previous work in cell culture has shown that various polyamides can be used to modulate the transcriptional programs of oncogenic transcription factors. In this study, two hairpin polyamides with demonstrated activity against androgen receptor signaling in cell culture were administered to mice to characterize their pharmacokinetic properties. Methods Py-Im polyamides were administered intravenously by tail vein injection. Plasma, urine, and fecal samples were collected over a 24-h period. Liver, kidney, and lung samples were collected postmortem. Concentrations of the administered polyamide in the plasma, excretion, and tissue samples were measured using LC/MS/MS. The biodistribution data were analyzed by both non-compartmental and compartmental pharmacokinetic models. Animal toxicity experiments were also performed by monitoring weight loss after a single subcutaneous (SC) injection of either polyamide. Results The biodistribution profiles of both compounds exhibited rapid localization to the liver, kidneys, and lungs upon injection. Plasma distribution of the two compounds showed distinct differences in the rate of clearance, the volume of distribution, and the AUCs. These two compounds also have markedly different toxicities after SC injection in mice. Conclusions The variations in pharmacokinetics and toxicity in vivo stem from a minor chemical modification that is also correlated with differing potency in cell culture. The results obtained in this study could provide a structural basis for further improvement of polyamide activity both in cell culture and in animal models.

原文英語
頁(從 - 到)617-625
頁數9
期刊Cancer Chemotherapy and Pharmacology
70
發行號4
DOIs
出版狀態已發佈 - 10月 2012
對外發佈

ASJC Scopus subject areas

  • 腫瘤科
  • 毒理學
  • 藥理
  • 癌症研究
  • 藥學(醫學)

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