Dosing time-dependent nephrotoxicity of cyclosporin A during 21-day administration to Wistar rats

Abstract

The incidence of cyclosporine A (CsA) nephrotoxicity with reference to the temporal stage of administration was studied during a chronic 21-day treatment in male Wistar rats. Oral administration (20 mg/kg/day) was given at four different times: 1, 7, 13, or 19 hours after light onset (HALO). Plasma creatinine and blood urea nitrogen (BUN) levels were determined at regular intervals over the 24 h: before treatment (day 0); 7, 14, and 21 days after the beginning of treatment (days 7, 14, and 21); and 7 and 14 days after CsA withdrawal (days 28 and 35). At the same times, creatinine clearance and g-glutamyl transferase urinary excretion were determined in the groups of animals treated at 7 and 19 HALO. Residual concentrations of CsA in the renal tissue were measured at the end of the treatment period (day 21) in all groups. Nephrotoxicity of CsA was dependent on the temporal stage of administration. The renal vasoconstriction showed by the increase in plasma creatinine and BUN levels and the decrease in creatinine clearance was maximal when the CsA was given at 7 and 19 HALO and was correlated to the tissue concentrations of CsA. Tubular injury seems to occur earlier and the return to normal function less rapidly in animals treated at 19 HALO compared with animals treated at 7 HALO.

Change From Cyclosporine to Combination Therapy of Mycophenolic Acid With the New Sphingosine-1-phosphate Receptor Agonist, KRP-203, Prevents Host Nephrotoxicity and Transplant Vasculopathy in Rats

“…This is consistent with reports from us and others in which oral CsA administration induced renal impairment in non-transplanted rats. [33][34][35] A switch to other treatments (MPA, KRP-203 and the combination) or cessation of CsA completely reversed the renal dysfunction and prevented histologic alteration due to CsA-induced nephrotoxicity at the end-point. However, the reversal of nephrotoxicity was independent of the type of regimen following CsA (MPA, KRP, MPA ϩ KRP, vehicle).…”

Time-Dependent Effect of Cyclosporine on Mitogenic Responses and Lymphocyte Subset Populations in Rat Spleen and Submaxillary Lymph Nodes

“…The chronopharmacology of cyclosporine, an immunosuppressant widely used to avert allograft rejection and in the therapy of autoimmune disorders, has been examined in animals [1][2][3][4][5][6][7][8] and in patients [9][10][11][12][13]. For example, in rats treated with Freund's adjuvant, we recently reported the existence of dosing-time-dependent effects of cyclosporine in lymph nodes, a 5-mg dose of cyclosporine causing a dose-dependent decrease in submaxillary lymph node ornithine decarboxylase activity (an indicator of cell proliferation) and an increase in presynaptic norepinephrine uptake only when injected during the resting phase of the diurnal cycle (i.e.…”