Mycophenolic acid predose concentrations and renal function in a mouse model for progressive renal fibrosis.
Within the scope of this study, the potential antifibrotic effect of mycophenolate mofetil (MMF) on COL4A3-deficient mice as an animal model for progressive renal fibrosis was investigated regarding kidney function and survival. Thirty-five animals were randomly assigned to one of five groups and treated with doses of 0, 10, 50, 100, or 150 mg/kg MMF per day, respectively. When increasing somnolence was observed, indicating end-stage renal disease, the mice were euthanized and blood was obtained. Serum concentrations of creatinine, urea nitrogen, total protein, mycophenolic acid (MPA), and mycophenolic acid glucuronide (MPAG) were quantified. The kidney histology was examined using hematoxylin and eosin as well as trichrome staining. The mean overall survival was 65.9 (+/-6.1) days with no significant difference between the treatment groups (P > 0.05, Mantel-Cox test). Serum predose concentrations of MPA and MPAG showed considerable interindividual variability. There was no correlation between survival time and MPA or MPAG concentrations (P > 0.05, Spearman rank correlation). However, an apparent decrease in serum creatinine and urea nitrogen concentrations was observed at higher doses of MMF, eg, -54% for creatinine in the 150-mg/kg/day group compared with placebo. A highly significant reciprocal correlation between MPA concentrations and serum creatinine was demonstrated (P < 0.01, r = -0.655, Spearman rank correlation). In conclusion, MMF may be a candidate drug for preserving kidney function in progressive renal fibrosis.
Brandhorst
Gunnar
G
Department of Clinical Chemistry, University Hospital Goettingen, Goettingen, Germany. gunnar.brandhorst@med.uni-goettingen.de
Brehmer
Franziska
F
Petrova
Darinka T
DT
Gross
Oliver
O
Miosge
Nicolai
N
Armstrong
Victor W
VW
Oellerich
Michael
M
D000818:Animals; D001324:Autoantigens / Q000235:genetics*; D024141:Collagen Type IV / Q000235:genetics*; D004195:Disease Models, Animal; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D005355:Fibrosis; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D007674:Kidney Diseases / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D007677:Kidney Function Tests; D051379:Mice; D018345:Mice, Knockout; D009173:Mycophenolic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D015996:Survival Rate
D001324:Autoantigens; D024141:Collagen Type IV; D007166:Immunosuppressive Agents; C057112:type IV collagen alpha3 chain; D009173:Mycophenolic Acid