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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 All of these renal disorders induced by tacrolimus recovered completely or partially when the drug was withdrawn for 2 or 4 weeks.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.

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HCO-60, a polyoxyethylene castor oil derivative, is used as a solubilizer in the injectable formulations of lipophilic agents. This study was performed to examine the toxicity of HCO-60 in various experimental animals including dogs, monkeys, rabbits, guinea pigs and rats. With 1.25 or 2.5 mg/kg of HCO-60 injected i.v. to dogs, blood pressure decreased, flush, swelling and itching appeared after injection, and with 10 mg/kg of HCO-60 there was additionally a decrease of spontaneous motility. In the two higher dose groups, these symptoms paralleled an increase of histamine levels. Since degranulation was observed after injection in the mast cells of the skin, but not in the liver of dogs, the histamine in the plasma was considered to be released from the mast cells of the skin. Pretreatment with diphenhydramine, a H1-receptor antagonist, suppressed the decrease of blood pressure induced by HCO-60. These findings show that the toxicity of HCO-60 is associated with histamine release from the mast cells. No symptoms occurred in monkeys, rabbits, guinea pigs or rats with 50 or 100 mg/kg of i.v. of HCO-60, and there was no change in plasma histamine levels. This study demonstrated that the toxicity of HCO-60 is species specific to dogs among the animals tested.