Preclinical study of pharmacokinetics and toxicokinetics of innovative peptide drug metilin

Relevance. Chronic heart failure (CHF) is one of the leading causes of cardiovascular mortality in Russia and abroad. Objective. To investigate the pharmacokinetic and toxicokinetic properties of a formulation of metilin, developed for the treatment of CHF. Materials and methods. Peptide metilin (H-(NαMe)Arg-Pro-Arg-Leu-Ser-His-Lys-Gly-Pro-Nle-Pro-Phe-OH) was obtained by automated solid-phase synthesis using Fmoc-methodology. The drug was purified by high-performance liquid chromatography (HPLC), and its chemical structure was characterized using 1H-NMR spectroscopy and ESI-MC mass spectrometry. Metilin concentration in rabbit plasma was determined using high-performance liquid chromatography with tandem mass-selective detection (HPLC MS/MS). Results. A pharmacokinetic study showed that metilin is characterized by a short residence time in the body (half-life 5.13±2.9 min, mean residence time 6.86±3.86 min) and a low volume of distribution (2.70±1.07 L/kg). When assessing the linearity of the concentration/dose response, higher values were noted for 1 mg/kg than for 5 mg/kg and 10 mg/kg, which is likely due to saturation of metilin binding to transport proteins. With repeated administration for 30 days, a statistically significant increase in AUC and a change in the elimination pattern were observed, indicating metilin accumulation in tissues; however, no significant toxic effects or physiological abnormalities in the condition of the animals were noted. Conclusion. The study's results demonstrate rapid elimination and predictable dose-dependent accumulation of metilin during long-term administration, indirectly confirming its favorable toxicokinetic profile. Based on these data, phase I clinical trials of the drug can be planned.