Systemic toxicity of tacrolimus given by various routes and the response to dose reduction.

Purpose: To evaluate the long-term systemic toxicity of tacrolimus (FK-506) administered by various routes, and to assess the effect of dose reduction on toxicity.

Methods: The study animals were 120 experimentally naive adult female Wistar rats weighing 200-250 g each. The rats were randomly divided into 10 equal groups (n=12 in each) and treated with tacrolimus administered topically (in drops, 0.3%, q.i.d.), intravitreally (0.5 mg/kg bodyweight/week), intramuscularly (1 mg/kg bodyweight/week), low-dose intravenously (1 mg/kg bodyweight/week) and in high-dose intravenously (2 mg/kg bodyweight/week) for 3 months. The rats in the control groups (one for each different route of administration) were treated with 0.9% NaCl. The blood concentration of tacrolimus, complete blood count and biochemistry parameters were measured each month for the 3-month study period.

Results: The rats in the control groups and experimental groups administered topical and intravitreal tacrolimus did not demonstrate any systemic toxic effects. The rats that developed certain toxic effects (hyperglycaemia, hyperkalaemia and nephrotoxicity) in the groups given low-dose or high-dose i.v. tacrolimus responded well to dose reduction. Following dose reduction, blood glucose concentrations decreased from 247.4 +/- 42.3 mg/dL to 189.6 +/- 37.9 mg/dL (P <0.05), and from 237.4 +/- 41.1 mg/dL to 182.3 +/- 22.7 mg/dL (P <0.05) in the low- and high-dose i.v. tacrolimus-treated rats, respectively. The rats that developed impaired hepatic function after high-dose tacrolimus did not respond to dose reduction. Baseline cholesterol concentrations for the intramuscular and low- and high-dose i.v. tacrolimus-treated groups, demonstrated decreases, respectively, from 87.4 +/- 14.0 mg/dL, 86.4 +/- 14.0 mg/dL and 90.4 +/- 14.3 mg/dL to 53.6 +/- 9.8 mg/dL, 52.1 +/- 12.5 mg/dL and 63.5 +/- 11.7 mg/dL by the end of the second month. The differences were found to be statistically significant (P <0.05 for each result).

Conclusion: Topical or intravitreal administration of tacrolimus seems to be systemically safe whereas parenteral administration can cause some systemic haematological changes such as dose-dependent decreased serum cholesterol concentrations. Dose reduction may prevent such adverse effects.