Acute toxicity evaluation of a thiazolo arene ruthenium (II) complex in rats

• Published in: Regulatory toxicology and pharmacology 2016-10, Vol.80, p.233-240
• Main Authors: Grozav, Adriana, Miclaus, Viorel, Vostinaru, Oliviu, Ghibu, Steliana, Berce, Cristian, Rotar, Ioana, Mogosan, Cristina, Therrien, Bruno, Loghin, Felicia, Popa, Daniela-Saveta
• Format: Article
• Language: English
• Subjects: Acute toxicity; Administration, Oral; Animals; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - toxicity; Arene ruthenium complexes; Biomarkers - blood; Body Weight - drug effects; Dose-Response Relationship, Drug; Female; Injections, Intraperitoneal; Lethal Dose 50; Models, Animal; Organometallic Compounds - administration & dosage; Organometallic Compounds - toxicity; Rats, Wistar; Risk Assessment; Ruthenium Compounds - administration & dosage; Ruthenium Compounds - toxicity; Spleen - drug effects; Spleen - pathology; Thiazole; Time Factors; Toxicity Tests, Acute - methods
• ISSN: 0273-2300; 1096-0295
• DOI: 10.1016/j.yrtph.2016.06.018

Recently, a series of thiazolo arene ruthenium complexes were found to be highly cytotoxic in vitro, on both cisplatin-sensitive and cisplatin-resistant ovarian cancer cells. The most active compound of the series, [(η6-p-cymene)Ru(L)Cl]Cl (L = 1-(2-(2-(3-chlorobenzylidene)hydrazinyl)-4-methylthiazol-5-yl)ethanone), was selected for an in vivo study in order to assess its safety profile. The ruthenium complex was administered to female Crl:WI rats orally, by gastric intubation and intraperitoneal injection. The hematological parameters and the histopathological changes in liver, kidneys, spleen and brain were investigated after a 14-days treatment. The substance was very well tolerated orally, with a LD50 value of over 2000 mg/kg body weight. Symptoms were observed only in the first day after intraperitoneal administration of the highest dose, with a LD50 value between 300 and 2000 mg/kg bw. The hematological profile was not modified at any of the tested doses, after both oral and intraperitoneal acute administration. Structural modifications (moderate lymphocytolysis) were identified only in the spleen at the highest tested dose. In conclusion, the thiazolo arene ruthenium complex was very well tolerated orally and had a low acute toxicity after intraperitoneal administration in Crl:WI rats The results justify further investigation to determine the in vivo therapeutic potential of this promising ruthenium complex. •The acute toxicity of a thiazolo arene ruthenium (II) complex was evaluated in rats.•The substance was very well tolerated orally.•The hematological profile was not modified at any of the tested doses.•Structural modifications were identified only in the spleen.