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Higher intracerebral concentration of tacrolimus after intermittent than continuous administration to rats
Author(s) -
Sakamoto Yoshihiro,
Makuuchi Masatoshi,
Harihara Yasushi,
Imamura Hiroshi,
Sato Hitoshi
Publication year - 2001
Publication title -
liver transplantation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.814
H-Index - 150
eISSN - 1527-6473
pISSN - 1527-6465
DOI - 10.1053/jlts.2001.28964
Subject(s) - tacrolimus , medicine , neurotoxicity , bolus (digestion) , pharmacokinetics , oral administration , anesthesia , transplantation , blood concentration , whole blood , trough concentration , pharmacology , urology , toxicity
Neurotoxicity associated with tacrolimus after liver transplantation is a serious problem. The optimal way to administer tacrolimus to reduce neurotoxicity remains to be clarified. Three groups of rats were administered tacrolimus for 2 weeks: group C, continuous intravenous infusion (0.25, 0.5, and 1.0 mg/kg/d); group I, intermittent intravenous bolus injection twice daily (0.25, 0.5, and 1.0 mg/kg/d); and group O, oral administration twice daily (5 mg/kg/d; n = 12 each). Rats were killed either day 7 or 14 to measure whole‐blood and intracerebral trough concentrations of tacrolimus. The area under the whole‐blood concentration‐time curve (AUC) was determined day 7. The relative risk ratio of neurotoxicity was evaluated on the basis of the brain to blood concentration ratio (Kp) and intracerebral concentration to AUC ratio (R AUC ). The whole‐blood concentration of tacrolimus and AUC value were greater in group C than group I. Conversely, the intracerebral concentration and Kp and R AUC values were significantly greater in group I than group C. The difference in Kp values between groups C and I significantly increased with the dose and duration of administration. Whole‐blood and intracerebral concentrations in group O were similar to those at the 0.25‐mg/kg/d dose in group I. In conclusion, the intracerebral concentration of tacrolimus was greater after intermittent than continuous administration of the drug. Continuous administration of tacrolimus might be more advantageous than the intermittent method to reduce the intracerebral concentration and neurotoxicity.