Several studies have shown the potential therapeutic utility of kinin B1 receptor (B1R) peptide agonists in neurological and ischemic cardiovascular diseases and brain cancer. Preclinical safety studies are a prerequisite for further drug development.
The objectives of this study were to determine the acute toxicity and pharmacokinetics of the peptide B1R agonist, SarLys[DPhe8]desArg9-bradykinin (NG29), as trifluoroacetate (TFacetate) or acetate salt form, following a single intravenous injection in the rat. A maximum tolerated dose (MTD) of NG29-TFacetate was established at 75 mg/kg from the results of a dose rangefinding study (up to 200 mg/kg). The short-term (4-day) repeat-dose toxicity study of NG29, using its MTD value, showed that NG29-acetate exhibited minimal non-adverse clinical pathology changes in hematology, coagulation, clinical chemistry and urine parameters and severe kidney histopathological changes characterized by renal tubular degeneration. No such effects were observed with NG29-TFacetate. At the injection site, NG29-TFacetate was considered to be more locally irritating when compared to the acetate form. The extent of exposure and half-life values of NG29-TFacetate were comparable to the acetate form (AUC0-α of 10. 2 mg/l*h vs. 9. 9 mg/l*h; T1/2 of 2. 3h vs. 2. 4h). This study shows that in rats NG29-TFacetate exhibits a superior tolerability profile compared with the peptide acetate form.
Biological chemistry. 2015 Nov 13 [Epub ahead of print]
Martin Savard, Jérôme Côté, Luc Tremblay, Witold Neugebauer, Domenico Regoli, Sébastien Gariépy, Nathalie Hébert, Fernand Gobeil