title: Safety and pharmacokinetics of a kinin B1 receptor peptide agonist produced with different counter-ions.
abstract: 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 intravenous injection in rats. A maximum tolerated dose (MTD) of NG29-TFacetate was established at 75 mg/kg from the results of a dose range-finding 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 2.3 h vs. 2.4 h). This study shows that in rats NG29-TFacetate exhibits a superior tolerability profile compared with the peptide acetate form.
authors.forename: Martin
authors.initials: M
authors.lastname: Savard
authors.forename: Jérôme
authors.initials: J
authors.lastname: Côté
authors.forename: Luc
authors.initials: L
authors.lastname: Tremblay
authors.forename: Witold
authors.initials: W
authors.lastname: Neugebauer
authors.forename: Domenico
authors.initials: D
authors.lastname: Regoli
authors.forename: Sébastien
authors.initials: S
authors.lastname: Gariépy
authors.forename: Nathalie
authors.initials: N
authors.lastname: Hébert
authors.forename: Fernand
authors.initials: F
authors.lastname: Gobeil
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D057809:HEK293 Cells; D006207:Half-Life; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D020714:Maximum Tolerated Dose; D010455:Peptides / Q000008:administration & dosage / Q000009:adverse effects* / Q000737:chemistry / Q000493:pharmacokinetics*; D051381:Rats; D017208:Rats, Wistar; D043783:Receptor, Bradykinin B1 / Q000819:agonists*
chemical_list: D010455:Peptides; D043783:Receptor, Bradykinin B1