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.