Safety and pharmacokinetics of a kinin B1 receptor peptide agonist produced with different counter-ions

Biol Chem. 2016 Apr;397(4):365-72. doi: 10.1515/hsz-2015-0246.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Dose-Response Relationship, Drug
  • HEK293 Cells
  • Half-Life
  • Humans
  • Injections, Intravenous
  • Male
  • Maximum Tolerated Dose
  • Peptides / administration & dosage
  • Peptides / adverse effects*
  • Peptides / chemistry
  • Peptides / pharmacokinetics*
  • Rats
  • Rats, Wistar
  • Receptor, Bradykinin B1 / agonists*

Substances

  • Peptides
  • Receptor, Bradykinin B1