title: Everolimus and sirolimus in combination with cyclosporine have different effects on renal metabolism in the rat.
abstract: Enhancement of calcineurin inhibitor nephrotoxicity by sirolimus (SRL) is limiting the clinical use of this drug combination. We compared the dose-dependent effects of the structurally related everolimus (EVL) and sirolimus (SRL) alone, and in combination with cyclosporine (CsA), on the rat kidney. Lewis rats were treated by oral gavage for 28 days using a checkerboard dosing format (0, 3.0, 6.0 and 10.0 CsA and 0, 0.5, 1.5 and 3.0 mg/kg/day SRL or EVL, n = 4/dose combination). After 28 days, oxidative stress, energy charge, kidney histologies, glomerular filtration rates, and concentrations of the immunosuppressants were measured along with (1)H-magnetic resonance spectroscopy (MRS) and gas chromatography- mass spectrometry profiles of cellular metabolites in urine. The combination of CsA with SRL led to higher urinary glucose concentrations and decreased levels of urinary Krebs cycle metabolites when compared to controls, suggesting that CsA+SRL negatively impacted proximal tubule metabolism. Unsupervised principal component analysis of MRS spectra distinguished unique urine metabolite patterns of rats treated with CsA+SRL from those treated with CsA+EVL and the controls. SRL, but not EVL blood concentrations were inversely correlated with urine Krebs cycle metabolite concentrations. Interestingly, the higher the EVL concentration, the closer urine metabolite patterns resembled those of controls, while in contrast, the combination of the highest doses of CsA+SRL showed the most significant differences in metabolite patterns. Surprisingly in this rat model, EVL and SRL in combination with CsA had different effects on kidney biochemistry, suggesting that further exploration of EVL in combination with low dose calcineurin inhibitors may be of potential benefit.
authors.affiliation: iC42 Clinical Research & Development, Department of Anesthesiology, University of Colorado Denver, Aurora, Colorado, USA.
authors.forename: Rahul
authors.initials: R
authors.lastname: Bohra
authors.forename: Wenzel
authors.initials: W
authors.lastname: Schöning
authors.forename: Jelena
authors.initials: J
authors.lastname: Klawitter
authors.forename: Nina
authors.initials: N
authors.lastname: Brunner
authors.forename: Volker
authors.initials: V
authors.lastname: Schmitz
authors.forename: Touraj
authors.initials: T
authors.lastname: Shokati
authors.forename: Ryan
authors.initials: R
authors.lastname: Lawrence
authors.forename: Maria Fernanda
authors.initials: MF
authors.lastname: Arbelaez
authors.forename: Björn
authors.initials: B
authors.lastname: Schniedewind
authors.forename: Uwe
authors.initials: U
authors.lastname: Christians
authors.forename: Jost
authors.initials: J
authors.lastname: Klawitter
mesh_terms: D000284:Administration, Oral; D000818:Animals; D016572:Cyclosporine / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D004359:Drug Therapy, Combination; D000068338:Everolimus; D005919:Glomerular Filtration Rate / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D028421:Isoprostanes / Q000652:urine; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D008297:Male; D018384:Oxidative Stress; D025341:Principal Component Analysis; D051381:Rats; D011917:Rats, Inbred Lew; D012044:Regression Analysis; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000633:toxicity*
chemical_list: D007166:Immunosuppressive Agents; D028421:Isoprostanes; D016572:Cyclosporine; D000068338:Everolimus; D020123:Sirolimus