title: Features and full reversibility of the renal toxicity of the ruthenium-based drug NAMI-A in mice.
abstract: The ruthenium-based compound imidazolium trans-imidazoledimethylsulfoxide-tetrachlororuthenate (NAMI-A) is free of cytotoxicity up to 1mM concentration after 1h in vitro exposure of the LLC-PK1 renal tubule cells. In vivo, one cycle of i.p. administrations of 35 mg/kg/day NAMI-A (1 cycle=6 consecutive days), is free of a measurable toxicity on mouse kidneys. After two cycles with a one-week drug-free washout between cycles, mitochondrial membrane potential of the renal cells drops by 37% (p<0.05), serum creatinine increases by 30% (p<0.05) and a significant decrease of body weight of 12% (p<0.05) occurs. These parameters return to normal within 7 days after the end of treatment. A cycle-dependent alteration of glomeruli and a diffused swelling of renal tubules are also evident leading to a significant alteration of these structures after the third cycle. These effects are completely prevented if a 2-week drug free washout is used between two consecutive cycles. These data support the toxic accumulation of NAMI-A or of its products of transformation in the kidneys and stress the need of at least 14 days washout between two treatment cycles when the drug is given daily for 6 consecutive days.
authors.affiliation: Department of Life Sciences, University of Trieste, via L. Giorgieri 7, 34127 Trieste, Italy.
authors.forename: Marta
authors.initials: M
authors.lastname: Vadori
authors.forename: Sabrina
authors.initials: S
authors.lastname: Pacor
authors.forename: Francesca
authors.initials: F
authors.lastname: Vita
authors.forename: Sonia
authors.initials: S
authors.lastname: Zorzet
authors.forename: Moreno
authors.initials: M
authors.lastname: Cocchietto
authors.forename: Gianni
authors.initials: G
authors.lastname: Sava
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D003404:Creatinine / Q000097:blood; D004121:Dimethyl Sulfoxide / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000633:toxicity; D007274:Injections, Intraperitoneal; D007668:Kidney / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D007678:Kidney Glomerulus / Q000187:drug effects* / Q000473:pathology; D007684:Kidney Tubules / Q000187:drug effects* / Q000473:pathology; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008808:Mice, Inbred CBA; D009942:Organometallic Compounds / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D017975:Ruthenium Compounds; D034421:Sus scrofa; D014018:Tissue Distribution; D015431:Weight Loss / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D009942:Organometallic Compounds; D017975:Ruthenium Compounds; C113661:imidazolium-bis(imidazole)dimethylsulfoxideimidazotetrachlororuthenate(III); D003404:Creatinine; D002945:Cisplatin; D004121:Dimethyl Sulfoxide