Single-dose pharmacokinetic and toxicity analysis of pyrrole-imidazole polyamides in mice.
OBJECTIVE
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.
Department of Molecular Pharmacology, Beckman Research Institute of the City of Hope, Duarte, CA 91010, USA.
Timothy W
TW
Synold
Bixin
B
Xi
Jun
J
Wu
Yun
Y
Yen
Benjamin C
BC
Li
Fei
F
Yang
John W
JW
Phillips
Nicholas G
NG
Nickols
Peter B
PB
Dervan
D000818:Animals; D005260:Female; D007093:Imidazoles / Q000493:pharmacokinetics* / Q000633:toxicity; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009757:Nylons / Q000493:pharmacokinetics* / Q000633:toxicity; D011758:Pyrroles / Q000493:pharmacokinetics* / Q000633:toxicity; D014018:Tissue Distribution
D007093:Imidazoles; D009757:Nylons; D011758:Pyrroles