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

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)617-625
Number of pages9
JournalCancer Chemotherapy and Pharmacology
Volume70
Issue number4
DOIs
Publication statusPublished - Oct 1 2012
Externally publishedYes

Fingerprint

Pyrroles
Pharmacokinetics
Nylons
Toxicity
Cell culture
Cell Culture Techniques
Subcutaneous Injections
Plasmas
Liver
Animals
Kidney
Lung
Injections
Chemical modification
Androgen Receptors
imidazole
Area Under Curve
Tail
Weight Loss
Veins

Keywords

  • Biodistribution
  • Mice
  • Pharmacokinetics
  • Py-Im polyamides
  • Toxicity

ASJC Scopus subject areas

  • Oncology
  • Toxicology
  • Pharmacology
  • Cancer Research
  • Pharmacology (medical)

Cite this

Single-dose pharmacokinetic and toxicity analysis of pyrrole-imidazole polyamides in mice. / Synold, Timothy W.; Xi, Bixin; Wu, Jun; Yen, Yun; Li, Benjamin C.; Yang, Fei; Phillips, John W.; Nickols, Nicholas G.; Dervan, Peter B.

In: Cancer Chemotherapy and Pharmacology, Vol. 70, No. 4, 01.10.2012, p. 617-625.

Research output: Contribution to journalArticle

Synold, TW, Xi, B, Wu, J, Yen, Y, Li, BC, Yang, F, Phillips, JW, Nickols, NG & Dervan, PB 2012, 'Single-dose pharmacokinetic and toxicity analysis of pyrrole-imidazole polyamides in mice', Cancer Chemotherapy and Pharmacology, vol. 70, no. 4, pp. 617-625. https://doi.org/10.1007/s00280-012-1954-3
Synold, Timothy W. ; Xi, Bixin ; Wu, Jun ; Yen, Yun ; Li, Benjamin C. ; Yang, Fei ; Phillips, John W. ; Nickols, Nicholas G. ; Dervan, Peter B. / Single-dose pharmacokinetic and toxicity analysis of pyrrole-imidazole polyamides in mice. In: Cancer Chemotherapy and Pharmacology. 2012 ; Vol. 70, No. 4. pp. 617-625.
@article{73efd2fee066486dae56a65208a3788f,
title = "Single-dose pharmacokinetic and toxicity analysis of pyrrole-imidazole polyamides in mice",
abstract = "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.",
keywords = "Biodistribution, Mice, Pharmacokinetics, Py-Im polyamides, Toxicity",
author = "Synold, {Timothy W.} and Bixin Xi and Jun Wu and Yun Yen and Li, {Benjamin C.} and Fei Yang and Phillips, {John W.} and Nickols, {Nicholas G.} and Dervan, {Peter B.}",
year = "2012",
month = "10",
day = "1",
doi = "10.1007/s00280-012-1954-3",
language = "English",
volume = "70",
pages = "617--625",
journal = "Cancer Chemotherapy and Pharmacology",
issn = "0344-5704",
publisher = "Springer Verlag",
number = "4",

}

TY - JOUR

T1 - Single-dose pharmacokinetic and toxicity analysis of pyrrole-imidazole polyamides in mice

AU - Synold, Timothy W.

AU - Xi, Bixin

AU - Wu, Jun

AU - Yen, Yun

AU - Li, Benjamin C.

AU - Yang, Fei

AU - Phillips, John W.

AU - Nickols, Nicholas G.

AU - Dervan, Peter B.

PY - 2012/10/1

Y1 - 2012/10/1

N2 - 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.

AB - 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.

KW - Biodistribution

KW - Mice

KW - Pharmacokinetics

KW - Py-Im polyamides

KW - Toxicity

UR - http://www.scopus.com/inward/record.url?scp=84867582231&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84867582231&partnerID=8YFLogxK

U2 - 10.1007/s00280-012-1954-3

DO - 10.1007/s00280-012-1954-3

M3 - Article

C2 - 22907527

AN - SCOPUS:84867582231

VL - 70

SP - 617

EP - 625

JO - Cancer Chemotherapy and Pharmacology

JF - Cancer Chemotherapy and Pharmacology

SN - 0344-5704

IS - 4

ER -