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COMPARATIVE EVALUATION OF METHOTREXATE TOXICITY AS SOLUTION FOR INJECTION AND LIPOSOMES FOLLOWING A SHORT-TERM TREATMENT IN A MURINE MODEL OF ARTHRITIS. NOTE I. HAEMATOLOGICAL AND BIOCHEMICAL EVALUATION

BÂRCĂ MARIA¹, BACONI DANIELA LUIZA^1*, CIOBANU ANNEMARIE¹, BURCEA GEORGE TRAIAN ALEXANDRU¹, BĂLĂLĂU CRISTIAN²

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The aim of this study was the evaluation of the toxicity of methotrexate (MTX)- loaded liposomes, comparatively with MTX injectable solution, following a short-term treatment in a rat model of arthritis (Freund’s adjuvant induced). We prepared liposomes with MTX itself ("hydrophobic MTX") and with its disodium salt ("hydrosoluble MTX"). The intracellular transport of liposomes has been evaluated in vitro on RAW267.4 tumour murine macrophages by fluorescence microscopy using DilC18(3) as fluorescent probe. Three different doses of MTX preparations (0.2 mg/kg b.w., 0.3 mg/kg b.w. and 0.4 mg/kg b.w.) have been intravenously (i.v.) administered once a week for three weeks. The influence of MTX treatment was evaluated on the haematological parameters and on some biochemical parameters (relevant for the liver and kidney function). Moderate decrease of haemoglobin and hematocrit was observed 14 days after the last MTX dose in the rats treated with low and intermediate doses of MTX –injectable solution and hydrosoluble MTX-loaded liposomes doses. The leukocyte formula was impaired, predominantly 7 days after the last MTX dose; an increase of the granulocyte count associated with a decrease of the monocyte count were noticed, indicating an equilibrating mechanism for the phagocytes. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities were low and irregularly affected, with a moderate increase of the AST values following high MTX doses. Other serum biochemical parameters (glucose, bilirubin, creatinine and urea levels) showed no significant differences compared with the control group. The results of the study suggest that MTX-loaded liposomes treatment has a reduced toxicity, comparatively with MTX injectable solution treatment in a murine model of arthritis.