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

  • Kazuhiro TadaEmail author
  • Yukio Iwashita
  • Ken Shiraiwa
  • Hiroki Uchida
  • Yusuke Oshima
  • Yuhki Sato
  • Hiroaki Nakanuma
  • Teijiro Hirashita
  • Takashi Masuda
  • Yuichi Endo
  • Yu Takeuchi
  • Masayuki Ohta
  • Hiroki Itoh
  • Masafumi Inomata
Original Article
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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.

Keywords

5-fluorouracil Major hepatectomy Dihydropyrimidine dehydrogenase Pharmacokinetics 

Notes

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.

Compliance with ethical standards

Conflict of interest

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

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Kazuhiro Tada
    • 1
    Email author
  • Yukio Iwashita
    • 1
  • Ken Shiraiwa
    • 2
  • Hiroki Uchida
    • 1
  • Yusuke Oshima
    • 1
    • 3
    • 4
  • Yuhki Sato
    • 2
  • Hiroaki Nakanuma
    • 1
  • Teijiro Hirashita
    • 1
  • Takashi Masuda
    • 1
  • Yuichi Endo
    • 1
  • Yu Takeuchi
    • 1
  • Masayuki Ohta
    • 1
    • 5
  • Hiroki Itoh
    • 2
  • Masafumi Inomata
    • 1
  1. 1.Faculty of Medicine, Department of Gastroenterological and Pediatric SurgeryOita UniversityOitaJapan
  2. 2.Department of Clinical PharmacyOita University HospitalOitaJapan
  3. 3.Biomedical Optics LaboratoryGraduate School of Biomedical Engineering Tohoku UniversityMiyagiJapan
  4. 4.Oral-Maxillofacial Surgery and OrthodonticsUniversity of Tokyo HospitalTokyoJapan
  5. 5.Global Oita Medical Advanced Research Center for HealthOita UniversityOitaJapan

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