Skip to main content

Advertisement

SpringerLink
Log in

Assessment of pharmacokinetic variations of capecitabine after multiple administration in rats: a physiologically based pharmacokinetic model

  • Original Article
  • Published:
Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

Capecitabine is a prodrug of 5-fluorouracil (5-FU) used for the treatment of colorectal cancer, with a two-week course of administration. However, the variance in plasma concentration and metabolic enzyme activities after multiple administration of capecitabine and its metabolites is unknown. The aim of this study was to identify the variance and predict the plasma concentration profile of capecitabine and its metabolites, using metabolic enzyme activities, to develop a more effective and safer medication.

Methods

Rats orally received 180 mg/kg of capecitabine once a day for two weeks. Blood samples were collected nine times, and plasma concentration was measured on day 1, 7, and 14. The liver and small intestine were removed after blood sampling and were used in vitro to evaluate metabolic enzyme activities of carboxylesterase, cytidine deaminase, and thymidine phosphorylase. A physiologically based pharmacokinetic (PBPK) model was developed using in vitro results.

Results

Area under the plasma concentration–time curve from 0 h to infinity of 5-FU on day 7 and day 14 was significantly lower than that on day 1. Intrinsic clearance of thymidine phosphorylase in the liver on day 7 and day 14 was 1.4 and 1.3 times lower than that on day 1, respectively. The PBPK model described the observed plasma concentration of capecitabine and its metabolites.

Conclusion

The decreased plasma concentration of capecitabine was caused by decreased metabolic enzyme activity. Efficacy can be improved by dose adjustment of capecitabine based on metabolic enzyme activities, using the PBPK model.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Saif MW, Choma A, Salamone SJ, Chu E (2009) Pharmacokinetically guided dose adjustment of 5-fluorouracil: a rational approach to improving therapeutic outcomes. J Natl Cancer Inst 101:1543–1552

    Article  CAS  Google Scholar 

  2. Lee JJ, Beumer JH, Chu E (2016) Therapeutic drug monitoring of 5-fluorouracil. Cancer Chemother Pharmacol 78:447–464

    Article  CAS  Google Scholar 

  3. Cassidy J, Clarke S, Diaz-Rubio E, Scheithauer W, Figer A, Wong R, Koski S, Lichinitser M, Yang TS, Rivera F, Couture F, Sirzen F, Saltz L (2008) Randomized phase III study of capecitabine plus oxaliplatin compared with fluorouracil/folinic acid plus oxaliplatin as first-line therapy for metastatic colorectal cancer. J Clin Oncol 26:2006–2012

    Article  CAS  Google Scholar 

  4. Guo Y, Xlong BH, Zhang T, Cheng Y, Ma L (2016) XELOX vs. FOLFOX in metastatic colorectal cancer: an updated meta-analysis. Cancer Invest 34:94–104

    Article  CAS  Google Scholar 

  5. Van Cutsem E, Twelves C, Cassidy J, Allman D, Bajetta E, Boyer M, Bugat R, Findlay M, Frings S, Jahn M, McKendrick J, Osterwalder B, Perez-Manga G, Rosso R, Rougier P, Schmiegel WH, Seitz JF, Thompson P, Vieitez JM, Weitzel C, Harper P (2001) Oral capecitabine compared with intravenous fluorouracil plus leucovorin in patients with metastatic colorectal cancer: results of a large phase III study. J Clin Oncol 19:4097–4106

    Article  Google Scholar 

  6. Miwa M, Ura M, Nishisa M, Sawada N, Ishikawa T, Mori K, Shimma N, Umeda I, Ishitsuka H (1998) Design of a novel oral fluoropyrimidine carbamate, capecitabine, which generates 5-fluorourcil selectivity in tumors by enzymes concentrated in human liver and cancer tissue. Eur J Cancer 34:1274–1281

    Article  CAS  Google Scholar 

  7. Shimma N, Umeda I, Arasaki M, Murasaki C, Masubuchi K, Kohchi Y, Miwa M, Ura M, Sawada N, Tahara H, Kuruma I, Horii I, Ishitsuka H (2000) The design and synthesis of a new tumor-selective fluoropyrimidine carbamate, capecitabine. Bioorg Med Chem 8:1697–1706

    Article  CAS  Google Scholar 

  8. Blesch KS, Gieschke R, Tsukamoto Y, Reigner BG, Burger HU, Steimer JL (2003) Clinical pharmacokinetic modeling in new drug development: the capecitabine experience. Invest New Drugs 21:195–223

    Article  CAS  Google Scholar 

  9. Meropol NJ (1998) Oral fluoropyrimidines in the treatment of colorectal cancer. Eur J Cancer 34:1509–1513

    Article  CAS  Google Scholar 

  10. Pilanci KN, Saglam S, Okyar A, Yucel S, Pala-Kara Z, Ordu C, Namal E, Ciftci R, Iner-Koksal U, Kaytan-Saglam E (2016) Chronomodulated oxaliplatin plus Capecitabine (XELOX) as a first line chemotherapy in metastatic colorectal cancer: a Phase II Brunch regimen study. Cancer Chemother Pharmacol 78:143–150

    Article  CAS  Google Scholar 

  11. Shindoh H, Kawashima A, Shishido N, Nakano K, Kobayashi K, Horii I (2006) Relationship between AUC of 5′-DFUR and toxicity of capecitabine, fluoropyrimidine carbamate analogs, and 5′-DFUR in monkeys, mice, and rats. J Toxicol Sci 31:265–285

    Article  CAS  Google Scholar 

  12. Kobuchi S, Yazaki Y, Ito Y, Sakaeda T (2018) Circadian variations in the pharmacokinetics of capecitabine and its metabolites in rat. Eur J Phaarm Sci 112:152–158

    Article  CAS  Google Scholar 

  13. Shindoh H, Nakano K, Yoshida T, Ishida M (2011) Comparison of in vitro conversion of capecitabine to 5-FU in rats, mice, monkeys and humans: toxicological implications. J Toxicol Sci 36:411–422

    Article  CAS  Google Scholar 

  14. Quick DJ, Shuler ML (1999) Use of in vitro data for construction of a physiologically based pharmacokinetic model for naphthalene in rats and mice to probe species differences. Biotechnol Prog 15:540–555

    Article  CAS  Google Scholar 

  15. Ikenaka K, Shirasaka T, Kitano S, Fujii S (1979) Effect of uracil on metabolism of 5-fluorouracil in vitro. GANN 70:353–359

    CAS  PubMed  Google Scholar 

  16. Tsukamoto Y, Kato Y, Ura M, Horii I, Ishitsuka H, Kusuhara H, Sugiyama Y (2001) A physiologically based pharmacokinetic analysis of capecitabine, a triple prodrug og 5-FU, in humans: the mechanism for tumor-selective assumulation of 5-FU. Pharm Res 18:1190–1202

    Article  CAS  Google Scholar 

  17. Judson IR, Beale PJ, Trigo JM, Aherene W, Cromptom T, Jones D, Bush E, Reigner B (1999) A human capecitabine excretion balance and pharmacokinetic study after administration of a single oral dose of 14C-labelled drug. Invest New Drugs 17:49–56

    Article  CAS  Google Scholar 

  18. Davies B, Morris T (1993) Physiological parameters in laboratory animals and humans. Pharm Res 10:1093–1095

    Article  CAS  Google Scholar 

  19. Iwatsubo T, Suzuki H, Sugiyama Y (1997) Prediction of species differences (rats, dogs, humans) in the in vivo metabolic clearance of YM796 by the liver from in vitro data. J Pharmacol Exp Ther 283:462–469

    CAS  PubMed  Google Scholar 

  20. Hyodo I, Shirao K, Doi T, Hatake K, Arai Y, Yamaguchi K, Tamura T, Takemiya S, Takiuchi H, Nakagawa K, Mishima H (2006) A phase II study of the global dose and schedule of capecitabine in Japanese patients with metastatic colorectal cancer. Jpn J Clin Oncol 36:410–417

    Article  Google Scholar 

  21. Hishinuma E, Narita Y, Saito S, Maekawa M, Akai F, Nakanishi Y, Yasuda J, Nagasaki M, Yamamoto M, Yamaguchi H, Mano N, Hirasawa N, Hiratsuka M (2018) Functional characterization of 21 allelic variants of dihydropyrimidine dehydrogenase identified in 1,070 Japanese individuals. Drug Metab Dispos 46:1083–1090

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pharmacokinetics, Kyoto Pharmaceutical University, Kyoto, 607-8414, Japan

    Shuhei Sakai, Shinji Kobuchi, Yukako Ito & Toshiyuki Sakaeda

Authors
  1. Shuhei Sakai
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shinji Kobuchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yukako Ito
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Toshiyuki Sakaeda
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Toshiyuki Sakaeda.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All the experiments were approved by the institutional review board and performed in accordance with the Kyoto Pharmaceutical University Guidelines for Animal Experimentation.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary file1 (PPTX 56 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Sakai, S., Kobuchi, S., Ito, Y. et al. Assessment of pharmacokinetic variations of capecitabine after multiple administration in rats: a physiologically based pharmacokinetic model. Cancer Chemother Pharmacol 85, 869–880 (2020). https://doi.org/10.1007/s00280-020-04057-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00280-020-04057-5

Keywords

Search

Navigation