title: Severe tacrolimus toxicity in rabbits.
abstract: OBJECTIVE
  Tacrolimus is an effective immunosuppressant, safely administered in clinical practice by monitoring blood levels. In experimental transplants, many dosage regimens have been reported, often without such determinations. Anorexia and organ toxicity commonly occur. We report the toxic effects of tacrolimus in rabbits receiving intramuscular injections (1 mg/kg/d) and the subsequent dosage modifications that resulted in improved animal survival without toxic effects.
  
  
  METHODS
  To obtain nontoxic drug concentrations in the blood, 3 dosage regimens were required. Drug concentrations were targeted using therapeutic human values as a guide (range, 5-20 ng/mL). First, a group of 12 Dutch-Belted rabbits received vascularized femoral allografts and were treated with intramuscular dosages of tacrolimus (1 mg/kg/d) for 14 days. Subsequently, dosage reductions in 10 more rabbits, to 0.2 mg/kg/d for 14 days, were necessary. Finally, another group of 20 rabbits was treated with 0.08 mg/kg for 3 days, and then every other day thereafter. Weight loss > 30%, cardiopulmonary failure, and/or creatinine levels > 221 micromol/L were the criteria approved by our local Institutional Animal Care and Use Committee for euthanizing the animals. Treated animals were compared with 20 nonimmunosuppressed controls that underwent the same operation.
  
  
  RESULTS
  At an intramuscular dosage of 1 mg/kg/d, the mean tacrolimus blood level was 90.7 ng/mL. Ten of the 12 animals in the original group died or required euthanasia. At necropsy, renal failure, cardiac abnormalities, and pulmonary edema were found. The tacrolimus dosage of 0.2 mg/kg/d produced a mean tacrolimus blood level of 17.6 ng/mL; however, 8 of the subsequent 10 rabbits died when given this dosage. Ultimately, the 0.08 mg/kg regimen in 20 rabbits permitted survival of 18 animals with a mean tacrolimus blood level of 6.8 ng/mL. None of 20 nonimmunosuppressed controls died after surgery.
  
  
  CONCLUSIONS
  For successful immunosuppression, Dutch-Belted rabbits require intramuscular tacrolimus dosages lower those required in other rabbit breeds. This has not been reported previously. The 0.08 mg/kg/d dosage combined with intermittent drug level monitoring permits survival without significant complications.
authors.affiliation: Department of Orthopedic Surgery, Microvascular Research Laboratory, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Goetz A
authors.initials: GA
authors.lastname: Giessler
authors.forename: Naomi M
authors.initials: NM
authors.lastname: Gades
authors.forename: Patricia F
authors.initials: PF
authors.lastname: Friedrich
authors.forename: Allen T
authors.initials: AT
authors.lastname: Bishop
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D005269:Femur / Q000098:blood supply / Q000637:transplantation; D006085:Graft Survival; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000097:blood / Q000633:toxicity*; D007273:Injections, Intramuscular; D009026:Mortality; D011817:Rabbits; D013045:Species Specificity; D016019:Survival Analysis; D016559:Tacrolimus / Q000008:administration & dosage / Q000097:blood / Q000633:toxicity*
chemical_list: D007166:Immunosuppressive Agents; D016559:Tacrolimus