Pharmacokinetics of the promising antitumor peptide HLDF-6-AA (Ac-ThrGlyGluAsnHisArg-NH2) was studied using its uniformly tritiated derivative. Experiments were performed on male Wistar rats, Balb/c mice and Chinchilla rabbits. The tritium labeled peptide [3H]HLDF-6-AA with the molar radioactivity of 50 Ci/mmol was obtained by the reaction of high-temperature solid-state catalytic isotope exchange (HSCIE). Under intravenous bolus administration of HLDF-6-AA peptide to rats and rabbits, the characteristics of its pharmacokinetic profile in the blood were obtained and the values of the main pharmacokinetic parameters of HLDF-6-AA peptide, and its active metabolite HisArg-NH2 were calculated. It was shown that parameters of the retention time in the body and the rate of elimination for peptides HLDF-6-AA and HisArg-NH2 in rats and rabbits are close and in rats they are about 7 and 21 min, respectively. It was shown that repeated administration of the drug does not lead to a change in its regular cumulation and does not cause a change in its pharmacokinetics compared with a single administration. The linearity of the dependence of pharmacokinetic parameters on the amount of administered peptide in the range of 2–22 mg/kg was proved in experiments in rats. As a result of the study of the distribution of HLDF-6-AA peptide and its metabolite HisArg-NH2 between the blood and peripheral tissues of mice, it was shown that the maximum concentration of HLDF-6-AA peptide is observed in the kidney tissues and a somewhat smaller concentration in the omentum. It was found that 15–20 min after intraperitoneal administration of HLDF-6-AA to mice, the concentration of HisArg-NH2 peptide begins to exceed the concentration of HLDF-6-AA peptide, which is caused by its greater resistance to proteolytic hydrolysis. The highest concentration of HisArg-NH2 peptide is observed in the kidney and liver tissues.
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Conflict of Interests
The authors declare that they have no conflicts of interest.
Statement on the Welfare of Animals
All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.
Statement of Compliance with Standards of Research Involving Humans as Subjects
This article does not contain any studies involving humans as subjects of research.
Translated by D. Novikova
Abbreviations: HS, hydrogen spillover; HSCIE, high-temperature solid-state catalytic isotope exchange; HLDF, human leukocyte differentiation factor; HLDF-6-AA, N-acetyl C-amide of ThrGlyGluAsnHisArg peptide; HFBA, heptafluorobutyric acid.
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Zolotarev, Y.A., Dadayan, A.K., Kozik, V.S. et al. Pharmacokinetics of HLDF-6-AA Peptide in the Organism of Experimental Animals. Russ J Bioorg Chem 45, 514–521 (2019). https://doi.org/10.1134/S1068162019050145
- HLDF-6 peptide
- tritium labeled peptides