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

Purpose Pyrrole–imidazole (Py-Im) polyamides are pro-grammable, sequence-specific DNA minor groove–binding ligands. Previous work in cell culture has shown that various polyamides can be used to modulate the transcriptional pro-grams 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 intrave-nously by tail vein injection. Plasma, urine, and fecal samples were collected over a 24-h period. Liver, kidney, and lung samples were collected postmortem. Concentra-tions of the administered polyamide in the plasma, excre-tion, and tissue samples were measured using LC/MS/MS. The biodistribution data were analyzed by both non-com-partmental 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 com-pounds 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