Correlation between neurotoxic events and intracerebral concentration of tacrolimus in rats.

The neurotoxicity associated with tacrolimus is one of the major limitations for its administration after organ transplantation. This study investigated the correlation between neurotoxicity and the intracerebral concentration of tacrolimus. Rats were given one of three doses of tacrolimus (5, 10, and 20 mg/kg/d) orally twice a day for 2 weeks and neurotoxic events were observed. The rats were sacrificed on either day 7 or 14. The trough values of the whole blood and the corresponding intracerebral concentrations were then measured. None of the rats receiving dosage of 5 mg/kg/d showed any neurotoxic symptoms throughout the two-week test period. In rats receiving a dosage of 10 mg/kg/d, however, all seven surviving rats presented tremors or seizures during the second week. In rats receiving a dosage of 20 mg/kg/d, 40% of the rats presented tremors or seizures during the first week. The threshold concentration of tacrolimus in the brain resulting in neurotoxic events was therefore estimated as approximately 700 ng/g. At concentrations over this threshold value, the intensity of the neurological event increases with the concentrations of tacrolimus in the brain. Using a linear correlation between the whole blood and intracerebral concentrations (r=0.967) of tacrolimus, the pharmacological threshold for the whole blood trough level was estimated as approximately 20 ng/ml, which falls into the same value reported for the incidental threshold of neurotoxicity in renal transplant recipients [Böttiger et al., Br. J. Clin. Pharmacol., 48, 445--448 (1999)]. Therefore, it is suggested that the rat is a good animal model to quantitatively evaluate the risk of neurotoxicity associated with tacrolimus in human, and that frequent measurement of whole blood tacrolimus concentrations is important for predicting and preventing neurotoxic events.