Correlation between Neurotoxic Events and Intracerebral Concentration of Tacrolimus in Rats
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概要
- 論文の詳細を見る
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 tacroliums. 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 than 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) or tacroliums 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 [Bottiger 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.
- 公益社団法人日本薬学会の論文
- 2000-08-01
著者
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SATO Hitoshi
Department of Clinical and Molecular Pharmacokinetics/Pharmacodynamics, School of Pharmaceutical Sci
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Sugawara Yasuhiko
Hepato-biliary-pancreatic Surgery Division Artificial Organ And Transplantation Division Department
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Sakamoto Yoshihiro
Hepatobiliary And Pancreatic Surgery Division National Cancer Center Hospital
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Sakamoto Yoshihiro
Department Of Surgery National Cancer Center Hospital
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IMAMURA HIROSHI
Artificial Organ and Transplantation Division, Department of Surgery, Graduate School of Medicine, T
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Imamura Hiroshi
Department Of Surgery Tokyo Women's Medical University Daini Hospital
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Shiratori Yasushi
Department Of Gastroenterology Faculty Of Medicine The University Of Tokyo
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Sato Hitoshi
Department Of Cardiovascular Medicine Tohoku University Graduate School Of Medicine
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Sakamoto Y
Artificial Organ And Transplantation Surgery Division Department Of Surgery Graduate School Of Medic
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SAKAMOTO Yoshihiro
Artificial Organ and Transplantation Surgery Division, Department of Surgery, Graduate School of Med
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KAKUUCHI Masatoshi
Artificial Organ and Transplantation Surgery Division, Department of Surgery, Graduate School of Med
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HARIHARA Yasushi
Artificial Organ and Transplantation Surgery Division, Department of Surgery, Graduate School of Med
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Imamura H
Department Of Surgery Tokyo Women's Medical University Daini Hospital
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Harihara Y
Artificial Organ And Transplantation Surgery Division Department Of Surgery Graduate School Of Medic
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Kakuuchi Masatoshi
Artificial Organ And Transplantation Surgery Division Department Of Surgery Graduate School Of Medic
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Makuuchi Masatoshi
Artificia Organ And Transplantation Surgery Division Departmetn Of Surgery Graduate School Of Medici
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Sato Hitoshi
Department Of Clinical And Molecular Pharmacokinetics
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Sato Hitoshi
Department Of Cardiology Juntendo University School Of Medicine
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SATO Hitoshi
Department of Animal Science, Faculty of Agriculture, Tohoku University
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