Inhibition of intestinal microflora β-glucuronidase modifies the distribution of the active metabolite of the antitumor agent, irinotecan hydrochloride (CPT-11) in rats |
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Authors: | Kiyoshi Takasuna Takehiro Hagiwara Masaaki Hirohashi Michiyuki Kato Mamoru Nomura Eiichi Nagai Tsuyoshi Yokoi Tetsuya Kamataki |
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Affiliation: | (1) Drug Safety Research Laboratory, Daiichi Pharmaceutical Co., Ltd., 16-13 Kitakasai 1-chome, Edogawa-ku, Tokyo 134, Japan Tel. +81-(03)-3680-0151; Fax +81-(03)-5696-8607, JP;(2) Medical Product Management and Market Planning, Daiichi Pharmaceutical Co., Ltd., 16-13 Kitakasai 1-chome, Edogawa-ku, Tokyo 134, Japan, JP;(3) Division of Drug Metabolism, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060, Japan, JP |
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Abstract: | Purpose: SN-38, a metabolite of irinotecan hydrochloride (CPT-11), is considered to play a key role in the development of diarrhea as well as in the antitumor activity of CPT-11. We have previously found that the inhibition of β-glucuronidase, which hydrolyzes detoxified SN-38 (SN-38 glucuronide) to reform SN-38, in the lumen by eliminating the intestinal microflora with antibiotics, markedly ameliorates the intestinal toxicity of CPT-11 in rats. In this study we compared the disposition of CPT-11 and its metabolites in rats treated with and without antibiotics. Methods: Rats were given drinking water containing 1 mg/ml penicillin and 2 mg/ml streptomycin from 5 days before the administration of CPT-11 (60 mg/kg i.v.) and throughout the experiment. CPT-11, SN-38 glucuronide and SN-38 concentrations in the blood, intestinal tissues and intestinal luminal contents were determined by HPLC. Results: Antibiotics had little or no effect on the pharmacokinetics of CPT-11, SN-38 glucuronide or SN-38 in the blood, or in the tissues or contents of the small intestine, which has less β-glucuronidase activity in its luminal contents. In contrast, antibiotics markedly reduced the AUC1–24 h of SN-38 (by about 85%) in the large intestine tissue without changing that of CPT-11, and this was accompanied by a complete inhibition of the deconjugation of SN-38 glucuronide in the luminal contents. Conclusions: These results suggest that SN-38, which results from the hydrolysis of SN-38 glucuronide by β-glucuronidase in the intestinal microflora, contributes considerably to the distribution of SN-38 in the large intestine tissue, and that inhibition of the β-glucuronidase activity by antibiotics results in decreased accumulation of SN-38 in the large intestine. Received: 8 August 1997 / Accepted: 16 January 1998 |
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Keywords: | CPT-11 SN-38 SN-38 glucuronide Diarrhea β -Glucuronidase |
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