Pharmacokinetics of FK-506,a Novel Immunosuppressant, after Intravenous and Oral Administrations to Rats
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概要
- 論文の詳細を見る
A pharmacokinetic study of FK-506 (FK), a novel immunosuppressant being about hundred times more potent than cyclosporin A (CyA) in the in vitro experiment, has been performed in rats after intravenous and oral administrations at two doses, 1.0 and 5.0 mg/kg. As compared with CyA, plasma, bile, urine and lymph FK levels were determined by a fluorescence high-performance liquid chromatographic method with chemiluminescence detection. Non-compartment pharmacokinetic parameters were calculated by area/moment analysis. After the i.v. injection of FK at 1.0 and 5.0 mg/kg, the total plasma clearance, CL_<tot>, was 7.028±0.076 (mean±S.E.) and 7.651±0.755 ml/min, steady-state distribution volume, V_<d, ss>, was 4623±28 and 4201±529 ml/kg, elimination half-life at the terminal elimination phase, t<1/2β>, was 2.36±0.25 and 2.54±0.29 h, and the volume of the initial distribution space, V_1,was 1336±150 and 1065±115 ml/kg, respectively. By comparing the pharmacokinetic parameter with CyA, the CL_<tot> of FK is about three times greater than that of CyA. There is not a significant difference on t_<1/2β> between CyA and FK. V_1 and V_<d, ss> of FK are 4-5 times greater than that of CyA. Therefore, higher clearance of FK is ascribed not only to the faster elimination from the rat body but also to the greater distribution space in the body. The mean percentage of FK transferred into the thoracic lymphatics over 6 h were 0.09±0.02% (1.0 mg/kg) and 0.16±0.02% (5.0 mg/kg), respectively. As the mean percentages of FK excrcted into both the bile and urine for 6 h after i.v. injection were 0.0744±0.0177% and 0.0073±0.0018%, respectively, the main elimination pathway of this drug is thought to be the metabolism in the body. To the other groups of rats, FK was administered intraduodenally, 5.0 mg/kg, in two kinds of liquid preparations, and both the systemic and lymphatic availabilities were studied. The mean systemic availabilities of FK were 11.3% and 23.5% from the two preparations. The lymphatic availability of this drug over the experimental period, 6 h, was less than 0.2%. These results suggest that FK distributes more extensively in the rat body than CyA.
- 社団法人日本薬学会の論文
著者
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TANAKA Hirokazu
Department of Cardiology, Tokyo Medical University
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TAKADA Kanji
Department of Pharmacokinetics, Kyoto Pharmaceutical University
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Yoshikawa Hiroshi
Department Of Biopharmaceutics Kyoto Pharmaceutical University:exploratory Development Laboratories
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Yoshikawa H
Department Of Biopharmaceutics Kyoto Pharmaceutical University:exploratory Development Laboratories
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USUDA Hisato
Department of Biopharmaceutics, Kyoto Pharmaceutical University
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OHHASHI Mamoru
Department of Biopharmaceutics, Kyoto Pharmaceutical University
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MURANISHI Shozo
Department of Biopharmaceutics, Kyoto Pharmaceutical University
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Takada Kanji
Dep. Of Pharmacokinetics Kyoto Pharmaceutical Univ.
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Takada K
Department Of Biopharmaceutics Kyoto Pharmaceutical University:exploratory Development Laboratories
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Tatsumi T
Kyoto Univ. Kyoto Jpn
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Tanaka Hirokazu
Department Of Cardiology Tokyo Medical University
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Takada Kanji
Department Of Biopharmaceutics Kyoto Pharmaceutical University:exploratory Development Laboratories
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Usuda Hisato
Department Of Biopharmaceutics Kyoto Pharmaceutical University:exploratory Development Laboratories
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Takada K
Kyoto Pharmaceutical Univ. Kyoto Jpn
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Ohhashi Mamoru
Department Of Biopharmaceutics Kyoto Pharmaceutical University:exploratory Development Laboratories
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Tatsumi T
Department Of Physics Kyoto University
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Tanaka H
Kyoto Pharmaceutical Univ. Kyoto Jpn
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Muranishi Shozo
Department Of Biopharmaceutics Kyoto Pharmaceutical University:exploratory Development Laboratories
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Muranishi Shozo
Department Of Biopharmaceutics Kyoto Pharmaceutical University
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Tanaka Hirokazu
Department Of Applied Physics National Defense Academy
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Yoshikawa Hiroshi
Department of Applied Physics, Handai Frontier Research Center, and Venture Business Laboratory of Center for Advanced Science and Innovation, Osaka University, Suita, Osaka 565-0871, Japan
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