RELATIONSHIP BETWEEN AUC of 5'-DFUR AND TOXICITY OF CAPECITABINE, FLUOROPYRIMIDINE CARBAMATE ANALOGS, AND 5'-DFUR IN MONKEYS, MICE, AND RATS
スポンサーリンク
概要
- 論文の詳細を見る
Capecitabine is an oral fluoropyrimidine carbamate which is converted to 5-fluorouracil (5-FU) via 3 enzymatic step to 5'-deoxy-5-fluorocytidine (5'-DFCR), 5'-deoxy-5-fluorouridine (5'-DFUR), and finally 5-FU. We performed 4-week toxicity studies of capecitabine (N^4-pentyloxycarbonyl-5'-deoxy-5-fluorouridine), galocitabine (trimethoxybenzyl-5'-deoxy-5-fluorocytidine), 4 different fluoropyrimidine carbamate analogs (R=butyl, isopentyl, propyl, or phenethyl), and 5'-DFUR in cynomolgus monkeys with toxicokinetic measurements of intact molecules, 5'-DFCR, and 5'-DFUR. Four-week toxicity data for capecitabine in rats and mice were also obtained for comparison. Capecitabine, galocitabine, butyl, and isopentyl analogs showed similar toxicities in hematopoietic and intestinal organs at 1.0 mmol/kg and the AUCs of 5'-DFUR were approximately 40 to 60μg*hr/ml. These compounds showed slight toxicity at 0.5 mmol/kg and no toxicity at 0.1 mmol/kg, and AUCs of 5'-DFUR were approximately 30 and 5μg*hr/ml, respectively. Propyl and phenethyl analogs showed slight toxicity at 1.0 mmol/kg and no toxicity at 0.5 mmol/kg, and AUCs of 5'-DFUR were approximately 30 and 10μg*hr/ml, respectively. On the other hand, severe and slight-to-moderate toxicity was observed at 0.5 and 0.25 mmol/kg in 5'-DFUR-treated monkeys and AUCs of 5'DFUR were 35.6 and 5.2μg*hr/ml, respectively. In mice and rats, the toxicity of capecitabine was less than in monkeys relative to dose, but 5'-DFUR AUCs were almost the same. In conclusion, 5'-DFUR AUC correlated with toxicity following oral administration of capecitabine and its analogs in monkeys, mice, and rats, although this relationship is not seen in humans. Capecitabine was less toxic in monkeys than oral 5'-DFUR according to dose (mmol/kg) and 5'-DFUR AUC.
- 日本トキシコロジー学会の論文
- 2006-08-23
著者
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Kobayashi Kazuko
Research Compliance & Quality Assurance Coordination Department Research Division Chugai Pharmac
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SHINDOH Hidetoshi
Pre-clinical Research Department
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KAWASHIMA Akira
Safety Assessment Department
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SHISHIDO Nobuyuki
Safety Assessment Department
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NAKANO Kounosuke
Pre-clinical Research Department
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HORII Ikuo
Pfizer Global Research & Development, Nagoya Laboratories, Pfizer Inc.
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Horii Ikuo
Showa Univ. (department Of Biochemical Toxicology School Of Pharmaceutical Sciences)
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Horii Ikuo
Pfizer Global Research & Development Nagoya Laboratories Pfizer Inc.
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Horii Ikuo
Worldwide Safety Sciences Pgrd Nagoya Laboratories Pfizer Inc.
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Horii Ikuo
Worldwide Safety Sciences Pfizer Global Research & Development Nagoya Laboratories Pfizer Inc.
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Nakano Kohnosuke
Pre-clinical Research Department Research Division Chugai Pharmaceutical Co. Ltd.
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Nakano Kounosuke
Pre-clinical Research Department Research Division Chugai Pharmaceutical Co. Ltd. Fuji Gotemba Resea
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Shishido Nobuyuki
Safety Assessment Department Research Division Chugai Pharmaceutical Co. Ltd.
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Shishido Nobuyuki
Safety Assessment Department Research Division Chugai Pharmaceutical Co. Ltd. Fuji Gotemba Research
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Shindoh Hidetoshi
Department Of Toxicology And Pathology Department Of Pharmacokinetics And Metabolism Nippon Roche Re
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Kobayashi Kazuko
Research Compliance & Quality Assurance Coordination Department Research Division Chugai Pharmac
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Kawashima Akira
Department Of Toxicology And Pathology Department Of Pharmacokinetics And Metabolism Nippon Roche Re
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Horii Ikuo
Biochemical Toxicology School Of Pharmaceutical Sciences Showa University
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Shindoh Hidetoshi
Pre-clinical Res. Dep. Res. Div. Chugai Pharmaceutical Co. Ltd. Kamakura Res. Labs.
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