title: Toxicology of FK506 in the cynomolgus monkey: a clinical, biochemical, and histopathological study.
abstract: We investigated clinical, biochemical, and histopathological parameters in FK506-treated cynomolgus monkeys. Eight monkeys given oral FK506, 1 (n = 4) or 10 (n = 4) mg/kg daily, survived the 90 days of treatment apparently in good health and without significant changes in biochemical and histopathological parameters, as did 2 control monkeys except one monkey on 10 mg/kg/day FK506 orally, who was found to have a malignant lymphoma. In contrast, monkeys given intramuscular FK506 1 mg/kg daily (n = 4) had to be sacrificed at day 20, 25, 32, and 47 because of severe illness. They showed abnormal biochemical parameters (increased serum urea and aspartate aminotransferase activity) and major histopathological changes in the kidney (mesangial cell proliferation and acute tubular necrosis), pancreas (depletion of beta cells), liver (steatosis), and heart (cardiomyopathy). Intramuscular administration of 1 mg/kg daily resulted in serum levels ranging from 10 to 15 ng/ml, while oral administration at a dose of 1 or 10 mg/kg daily resulted in equal or even higher serum levels (range 2-70 ng/ml). Thus, the height of the serum trough level of FK506 using the enzyme immunoassay is not related to the toxicity of FK506 in cynomolgus monkeys.
authors: Department of Surgery, University Hospital Maastricht, Maastricht, The Netherlands.
authors: R M
authors: RM
authors: Wijnen
authors: B G
authors: BG
authors: Ericzon
authors: A T
authors: AT
authors: Tiebosch
authors: W A
authors: WA
authors: Buurman
authors: C G
authors: CG
authors: Groth
authors: G
authors: G
authors: Kootstra
mesh_terms: D000284:Administration, Oral; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D003404:Creatinine / Q000097:blood; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000633:toxicity; D007273:Injections, Intramuscular; D007515:Islets of Langerhans / Q000187:drug effects / Q000473:pathology; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D007683:Kidney Tubular Necrosis, Acute / Q000139:chemically induced; D008252:Macaca fascicularis; D023421:Models, Animal; D010919:Placebos; D013154:Spleen / Q000187:drug effects / Q000473:pathology*; D016559:Tacrolimus / Q000008:administration & dosage / Q000633:toxicity*
chemical_list: D007166:Immunosuppressive Agents; D010919:Placebos; D003404:Creatinine; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D016559:Tacrolimus