Pharmacokinetics of SN-38 [(+)-(4S)-4,11-Diethyl-4,9-dihydroxy-1H-pyrano [3', 4' : 6,7]-indolizino [1,2-b] quinoline-3,14 (4H, 12H)-dione], an Active Metabolite of Irinotecan, after a Single Intravenous Dosing of ^<14>C-SN-38 to Rats
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概要
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Irinotecan (CPT-11) is a camptothecin derivative used for the treatment of cancer. It is a prodrug that is metabolized to its active form, SN-38 [(+)-(4S)-4,11-diethyl-4,9-dihydroxy-1H-pyrano [3', 4' : 6,7]-indolizino [1,2-b] quinoline-3,14 (4H, 12H)-dione]. To clarify the pharmacokinetic difference between CPT-11 and SN-38,the plasma levels, tissue distribution and excretion of SN-38 were investigated after dosing rats with ^<14>C-labeled SN-38. The plasma radioactivity showed bi-exponential decay with a terminal half-life of 9.91h. TLC separation revealed that the plasma radioactivity consisted mainly of SN-38 at 5 min after dosing ; however, it was soon replaced with SN-38 glucuronide (SN-38 Glu) and an unknown metabolite (M-2). The half-life of unchanged SN-38 after dosing with SN-38 was about 7 min, which was much shorter than that after dosing with CPT-11 (2.8h) as reported previously. Its radioactivity was excreted mainly in feces (70.0% within 168h), and biliary excretion (64.1% within 48h) could account for the fecal excretion. The major component of urinary and biliary radioactivity was found by TLC to be SN-38. Whole body autoradiograms revealed that the tissue distribution of the radioactivity was low except in the liver and kidney. The radioactivity decreased rapidly and little was found in the body 24h after dosing. In conclusion, SN-38 was excreted rapidly from bile and showed poor tissue distribution. These characteristics lead to a shorter SN-38 half-life, more so than dosing with CPT-11.
- 公益社団法人日本薬学会の論文
- 1995-08-15
著者
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岡崎 治
第一製薬株式会社 創剤代謝研究所
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渥美 亮
Drug Metabolism & Analytical Chemistry Research Center Developmental Research Laboratories Daiic
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Atsumi Ryo
Drug Metabolism & Analytical Chemistry Research Center Developmental Research Laboratories Daiic
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Hakusui H
Daiichi Pharmaceutical Co. Ltd. Tokyo Jpn
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伯水 英夫
Developmental Research Laboratories Daiichi Pharmaceutical Co. Ltd.
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岡崎 治
Drug Metabolism & Analytical Chemistry Research Center, Developmental Research Laboratories, Daiichi
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伯水 英夫
Drug Metabolism & Analytical Chemistry Research Center, Developmental Research Laboratories, Daiichi
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