Assessment of functional safety of blood forming organs in research of toxicological properties of medicinal products (Review). Part 1. Features of the hematopoietic organs of laboratory animals. Mechanisms of hematotoxicity

INTRODUCTION. The blood contains a large quantity of active cells of the organism and is a basic target for potentially toxic substances. The regulatory documents of the Russian Federation and international recommendations provide a list of mandatory biochemical and hematological parameters, but they are insufficient for predicting drug-induced hepatotoxicity in vivo during preclinical studies. A review of new data on this issue and an update of the list of biomarkers will expand the capabilities for monitoring the condition of laboratory animals, enhance the sensitivity and specificity of assessing toxic effects on hematopoiesis in preclinical studies, and thereby contribute to improving the safety of medicinal products and the effectiveness of therapy. The review consists of two parts.

AIM. The study aimed to identify the differences between the hematopoietic organs of humans and laboratory animals in order to develop recommendations for preclinical studies using animal blood as a biomaterial.

DISCUSSION. The first part of the review shows the characteristics of the hematopoietic organs of humans and laboratory animals, indicating their characteristics compared to humans. It is discussed of mechanisms of hemotoxicity of various medicinal products. The paper discusses the mechanisms of development of hematotoxicity of drugs, among which 4 main ones can be distinguished: cytotoxic effects on hematopoietic progenitor cells; direct damage to mature cells;  indirect damage to blood or bone marrow cells due to undesirable immune reactions against and changes in the activity of cell surface receptors; change in the activity of enzyme systems necessary for the normal functioning of cells. Data on clinical blood analysis parameters of 8 species of laboratory animals: rodents (mouse, rat, hamster, guinea pig) and non-rodents (rabbit, macaque, pygmy pig, ferret) are summarized.

CONCLUSIONS. Some features in the structure and function of the hematopoietic organs compared to humans can lead to significant differences in the toxicological profile of the drug. It should be noted that a clinical blood test allows us to assess a significant number of manifestations of hematotoxicity of drugs that directly affect blood cells and their precursors. With an indirect effect of the medicinal product (through enzyme systems, effect on progenitor cells, appearance of antibodies, etc.), these data are insufficient and the use of additional markers is necessary in order to increase the predictive value of preclinical studies and the comparability of data with clinical studies.

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