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Pharmacokinetic and toxicodynamic evaluation of 5-fluorouracil administration after major hepatectomy in a rat model

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Abstract

Background

Chemotherapy after hepatectomy for colorectal liver metastasis has not been established, due to the toxic side effects, which are likely related to impaired drug clearance during liver regeneration. We investigated the pharmacokinetic and toxicodynamic evaluation of 5-fluorouracil (5-FU) during liver regeneration after major hepatectomy in a rat model.

Methods

Thirty-six male Wistar rats were divided into control (C), control with chemotherapy (CC), hepatectomy (H), and hepatectomy with chemotherapy (HC) groups. The CC and HC groups were administered 5-FU for 4 days. Plasma 5-FU, liver weight, and liver dihydropyrimidine dehydrogenase (DPD) were measured. The ileal villous height was measured to determine adverse effects.

Results

The area under the curve and maximum plasma concentration of 5-FU increased by up to 51% and 32%, respectively, in the HC group compared to the CC group. The liver regeneration rate was significantly lower in the HC group than in the H group (67.3 ± 7.4 vs 33.0 ± 5.7%, p < 0.001). The HC group had a significantly lower liver DPD than the CC group (4.4 ± 1.1 mg vs 6.9 ± 1.1 mg, p < 0.01). The HC group had a significantly lower ileal villous height than the CC group (253 ± 40 μm vs. 318 ± 36 μm, p < 0.05).

Conclusions

Reduction of the total liver DPD following major hepatectomy caused increased plasma 5-FU levels and 5-FU-associated toxicity.

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Acknowledgements

We would like to thank Yuiko Aso, Mayumi Wada, and Marino Teshima for their technical assistance with the experiments, and Kaori Yasuda for her excellent technical assistance and advice.

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Authors and Affiliations

  1. Faculty of Medicine, Department of Gastroenterological and Pediatric Surgery, Oita University, 1-1 Idaigaoka, Hasama-machi, Oita, 879-5593, Japan

    Kazuhiro Tada, Yukio Iwashita, Hiroki Uchida, Yusuke Oshima, Hiroaki Nakanuma, Teijiro Hirashita, Takashi Masuda, Yuichi Endo, Yu Takeuchi, Masayuki Ohta & Masafumi Inomata

  2. Department of Clinical Pharmacy, Oita University Hospital, Oita, Japan

    Ken Shiraiwa, Yuhki Sato & Hiroki Itoh

  3. Biomedical Optics Laboratory, Graduate School of Biomedical Engineering Tohoku University, Miyagi, Japan

    Yusuke Oshima

  4. Oral-Maxillofacial Surgery and Orthodontics, University of Tokyo Hospital, Tokyo, Japan

    Yusuke Oshima

  5. Global Oita Medical Advanced Research Center for Health, Oita University, Oita, Japan

    Masayuki Ohta

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  1. Kazuhiro Tada
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  2. Yukio Iwashita
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Correspondence to Kazuhiro Tada.

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Kazuhiro Tada and other co-authors have no conflicts of interest to declare.

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Tada, K., Iwashita, Y., Shiraiwa, K. et al. Pharmacokinetic and toxicodynamic evaluation of 5-fluorouracil administration after major hepatectomy in a rat model. Cancer Chemother Pharmacol 85, 345–352 (2020). https://doi.org/10.1007/s00280-019-03969-1

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  • DOI: https://doi.org/10.1007/s00280-019-03969-1

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