Tacrolimus (FK506)-induced nephrotoxicity in spontaneous hypertensive rats.
To clarify the profile of the tacrolimus (FK506)-induced nephrotoxicity and its mechanism, 1, 2 and 4 mg/kg/day of tacrolimus was administered intramuscularly (i.m.) to spontaneous hypertensive rats (SHR) for 2 weeks, and biochemical and pathological parameters were studied in the animals. The acute nephrotoxicity of tacrolimus was characterized as increase of blood urea nitrogen (BUN) and plasma creatinine (P-Cr) levels in the groups of 1 mg/kg/day and more, decrease of creatinine clearance (CCr) value in the groups of 2 mg/kg/day and more, and histopathologically luminal narrowing of the arteriole adjacent the glomerulus in the groups of 1 mg/kg/day and more. These changes were associated with an increase of plasma renin activity (PRA) and urinary thromboxane B2 content and decrease of 6-keto-prostagrandinF1 alpha (6-keto-PGF1 alpha) content. Nilvadipine, which is one of the Ca2+ antagonist and is known to have renal vasodilating activity, prevented both biochemical and histopathological changes due to tacrolimus. The results indicated that the acute nephrotoxicity of tacrolimus was derived from impairment of glomerular function associated with the constriction of the renal arteriole brought about by the drug. All of these renal disorders induced by tacrolimus recovered completely or partially when the drug was withdrawn for 2 or 4 weeks. Consequently, the acute nephrotoxicity of tacrolimus in SHR was considered to be reversible.
Mitamura
T
T
Toxicology Research Laboratories, Fujisawa Pharmaceutical Co., Ltd., Osaka, Japan.
Yamada
A
A
Ishida
H
H
Fujihira
S
S
Ohara
K
K
Noguchi
H
H
Mine
Y
Y
D015121:6-Ketoprostaglandin F1 alpha / Q000652:urine; D000818:Animals; D001160:Arterioles / Q000187:drug effects; D001806:Blood Urea Nitrogen; D003404:Creatinine / Q000097:blood; D006973:Hypertension / Q000150:complications*; D007668:Kidney / Q000187:drug effects*; D007674:Kidney Diseases / Q000139:chemically induced* / Q000378:metabolism; D008297:Male; D009543:Nifedipine / Q000031:analogs & derivatives / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR; D012077:Renal Artery / Q000187:drug effects; D012083:Renin / Q000097:blood; D016559:Tacrolimus / Q000633:toxicity*; D013929:Thromboxane B2 / Q000652:urine; D014661:Vasoconstriction / Q000187:drug effects
C035100:nilvadipine; D013929:Thromboxane B2; D015121:6-Ketoprostaglandin F1 alpha; D003404:Creatinine; D012083:Renin; D009543:Nifedipine; D016559:Tacrolimus