INVESTIGATION OF THE CYTOTOXICITY OF NEW AMIODARONE DERIVATIVES IN NORMAL HEPATOCYTE CULTURE

519 Volume 5, Issue 10: Special Issue (EJAR) ISSN: 2181-2020 MPHAPP THE 6TH INTERNATIONAL SCIENTIFIC AND PRACTICAL CONFERENCE “MODERN PHARMACEUTICS: ACTUAL PROBLEMS AND PROSPECTS” TASHKENT, OCTOBER 17, 2025 in-academy.uz INVESTIGATION OF THE CYTOTOXICITY OF NEW AMIODARONE DERIVATIVES IN NORMAL HEPATOCYTE CULTURE Khashimova Z.S. Salakhutdinova M.K. Kakhorova K.A. Uzbekov V.V., Oshchepkova Yu.I. Salikhov Sh.I. e-mail: [email protected] Republic of Uzbekistan, Tashkent 100125, 83 Mirzo Ulugbek Street, A.S. Sadykov Institute of Bioorganic Chemistry, Academy of Sciences of the Republic of Uzbekistan https://doi.org/10.5281/zenodo.17343802 Arrhythmias remain a pressing challenge in modern cardiology because of their high prevalence and the serious threat they pose to patient survival. Current antiarrhythmic drugs, although effective, are often associated with side effects involving the central nervous system, the gastrointestinal tract, and other organ systems. Amiodarone (Cordarone), one of the most widely used drugs in clinical practice, is particularly well known for its systemic toxicity. Its most severe adverse effect is pulmonary injury, but it also has toxic effects on the thyroid gland and the liver. These can range from asymptomatic increases in transaminase activity to severe liver failure requiring transplantation. Such limitations highlight the need to develop new forms of amiodarone with improved solubility and reduced toxicity. In earlier work, we developed supramolecular complexes of amiodarone with glycyrrhizic acid (GA) and with its monoammonium salt (MGA) at molar ratios of 1:2, 1:4, and 1:8. A comparative study on HeLa cells demonstrated that these modified forms had significantly lower toxicity compared with the native drug [1]. The present study was designed to evaluate the cytotoxicity of these complexes in a transplantable line of normal hepatocytes (Hep23). Hep23 cells were cultured in RPMI-1640 medium in a CO₂ incubator, exposed to the test compounds, and then incubated again under the same conditions. Cytotoxicity was assessed using the MTT assay, a method that measures cellular metabolic activity and viability [2]. Untreated cells (defined as 100% viability) and the antitumor drug cisplatin were used as controls. The experiments showed that the original amiodarone was highly toxic to hepatocytes at a concentration of 100 μg/mL; only 4.6% of cells survived. In contrast, amiodarone-GA complexes displayed markedly lower toxicity. At a 1:2 molar ratio, the toxicity was 20.31%; at 1:8, it fell to 5.44%. At a 1:4 ratio, no toxic effect was detected, and cell viability was essentially identical to the control (101.88%). Amiodarone–MGA complexes showed no significant cytotoxicity at any of the molar ratios tested (1:2, 1:4, or 1:8). Cell viability remained in the range of 97–135%, with the strongest proliferative effect observed at the 1:4 ratio, similar to the GA complexes. In summary, modified forms of amiodarone based on GA and MGA demonstrated substantially reduced toxicity toward healthy hepatocytes compared with the parent drug. These findings are consistent with our earlier results in the HeLa tumour cell line and further support the protective role of these ligands.