Pharmacokinetics of 5-fluorouracil and increased hepatic dihydropyrimidine dehydrogenase activity levels in 1,2-dimethylhydrazine-induced colorectal cancer model rats

  • Shinji KobuchiEmail author
  • Yukako Ito
  • Kae Okada
  • Kazuki Imoto
  • Kanji Takada
Original Paper


To investigate the hepatic dihydropyrimidine dehydrogenase (DPD) activity in colorectal cancer (CRC), which is critically important to create a patient-specific dosing regimen, we performed 5-FU pharmacokinetic studies in 1,2-dimethylhydrazine–induced CRC model rats (CRC rats). After rats received 5-FU intravenous (IV) bolus injections, the area under the plasma concentration–time curve (AUC) and elimination half-life (t 1/2) in CRC rats (10.02 ± 0.37 μg h mL−1, 0.30 ± 0.02 h, respectively) were significantly lower than that in control rats (13.46 ± 1.20 μg h mL−1, 0.52 ± 0.05 h, respectively), whereas total plasma clearance (CLtot) in CRC rats (2.01 ± 0.07 L h−1 kg−1) was significantly increased compared with that in control rats (1.54 ± 0.14 L h−1 kg−1). Conversely, the avoidance ratio of the hepatic first-pass effect was approximately 20 % lower than that in control rats. Of interest is that hepatic DPD activity levels and the dihydrouracil-uracil ratio (UH2/Ura ratio) in plasma, which may act as a potential biomarker to evaluate hepatic DPD activity levels, were significantly increased in CRC rats. These results suggest that the decrease of hepatic availability in CRC rats is brought about by the increase in intrinsic clearance induced by the increase in DPD activity, resulting in a decrease in AUC and t 1/2 and an increase in CLtot after 5-FU IV bolus injection. Along with a proper dosing regimen for patients with CRC, a hepatic DPD activity monitoring system, such as the determination of UH2/Ura ratio in plasma, is desirable.


Pharmacokinetics 5-fluorouracil Dihydropyrimidine dehydrogenase Colorectal cancer 1,2-dimethylhydrazine 



This study was supported in part by Grant-in-Aid for Scientific Research (C) (No.24590223) from MEXT (Ministry of Education, Culture, Sports, Science and Technology).


  1. Astellas Pharma Inc. (2011) Fluvoxamine (Luvox®) [Drug Information]Google Scholar
  2. Balant-Gorgia AE et al (1991) Clinical pharmacokinetics of clomipramine. Clin Pharmacokinet 20:447–462PubMedCrossRefGoogle Scholar
  3. Barrat MA et al (2003) Etude des variations circadiennes de l’activite de la dihydropyrimidine deshydrogenase (DPD) dans la muqueuse buccale chez des sujets volontaires sains. Pathol Biol (Paris) 51:191–193CrossRefGoogle Scholar
  4. Beuzeboc P et al (1996) Toxicite severe au 5-fluorouracile chez une femme traitee pour un cancer du sein, presentant une osteogenese imparfaite et un deficit en dihydropyrimidine dehydrogenase. Bull Cancer (Paris) 83:324–327Google Scholar
  5. Bird RP (1987) Observation and quantification of aberrant crypts in the murine colon treated with a colon carcinogen: preliminary findings. Cancer Lett 37:147–151PubMedCrossRefGoogle Scholar
  6. César IC et al (2012) A rapid HPLC-ESI-MS/MS method for determination of dihydrouracil/uracil ratio in plasma: evaluation of toxicity to 5-flurouracil in patients with gastrointestinal cancer. Ther Drug Monit 34(1):59–66PubMedCrossRefGoogle Scholar
  7. Chazal M et al (1996) Link between dihydropyrimidine dehydrogenase activity in peripheral blood mononuclear cells and liver. Clin Cancer Res 2:507–510PubMedGoogle Scholar
  8. Cheng H et al (1994) Pharmacokinetics and bioinversion of ibuprofen enantiomers in humans. Pharm Res 11:824–830PubMedCrossRefGoogle Scholar
  9. Delval L, Klastersky J (2002) Optic neuropathy in cancer patients. Report of a case possibly related to 5 fluorouracil toxicity and review of the literature. J Neurooncol 60:165–169PubMedCrossRefGoogle Scholar
  10. Early Breast Cancer Trialists’ Collaborative Group (2002) Multi-agent chemotherapy for early breast cancer. Cochrane Database Syst Rev 8(4):CD000487Google Scholar
  11. Evans AM et al (1989) Stereoselective plasma protein binding of ibuprofen enantiomers. Eur J Clin Pharmacol 36:283–290PubMedCrossRefGoogle Scholar
  12. Fukushima M et al (2003) Population study of expression of thymidylate synthase and dihydropyrimidine dehydrogenase in patients with solid tumors. Int J Mol Med 12(6):839–844PubMedGoogle Scholar
  13. Fuse E et al (1996) Hepatic extraction ratio of 5-fluorouracil in rats. Dose dependence and effect of uracil and interleukin-2. Biochem Pharmacol 52:561–568PubMedCrossRefGoogle Scholar
  14. Gamelin E et al (2008) Individual fluorouracil dose adjustment based on pharmacokinetic follow-up compared with conventional dosage: results of a multicenter randomized trial of patients with metastatic colorectal cancer. J Clin Oncol 26(13):2099–2105PubMedCrossRefGoogle Scholar
  15. Harari PM (1997) Why has induction chemotherapy for advanced head and neck cancer become a United States community standard of practice? J Clin Oncol 15:2050–2055PubMedGoogle Scholar
  16. Harris BE et al (1988) Circadian rhythm of rat liver dihydropyrimidine dehydrogenase. Possible relevance to fluoropyrimidine chemotherapy. Biochem Pharmacol 37:4759–4762PubMedCrossRefGoogle Scholar
  17. Harris BE et al (1990) Relationship between dihydropyrimidine dehydrogenase activity and plasma 5-fluorouracil levels with evidence for circadian variation of enzyme activity and plasma drug levels in cancer patients receiving 5-fluorouracil by protracted continuous infusion. Cancer Res 50:197–201PubMedGoogle Scholar
  18. Hung HY et al (2011) Effect of preoperative neutrophil-lymphocyte ratio on the surgical outcomes of stage II colon cancer patients who do not receive adjuvant chemotherapy. Int J Colorectal Dis 26:1059–1065PubMedCrossRefGoogle Scholar
  19. Ishikawa T et al (1998) Tumor selective delivery of 5-fluorouracil by capecitabine, a new oral fluoropyrimidine carbamate, in human cancer xenografts. Biochem Pharmacol 55:1091–1097PubMedCrossRefGoogle Scholar
  20. Jarugula VR et al (1997) Nonlinear pharmacokinetics of 5-fluorouracil in rats. J Pharm Sci 86:756–758PubMedCrossRefGoogle Scholar
  21. Jemal A et al (2011) Global cancer statistics. CA cancer. J Clin 61(2):69–90Google Scholar
  22. Jiang H et al (2004) Circadian rhythm of dihydrouracil/uracil ratios in biological fluids: a potential biomarker for dihydropyrimidine dehydrogenase levels. Br J Pharmacol 141:616–623PubMedCrossRefGoogle Scholar
  23. Kankesan J et al (2003) Effect of PSC 833, an inhibitor of P-glycoprotein, on 1,2-dimethylhydrazine-induced liver carcinogenesis in rats. Carcinogenesis 24:1977–1984PubMedCrossRefGoogle Scholar
  24. Karthik Kumar V et al (2009) Modifying effects of morin on the development of aberrant crypt foci and bacterial enzymes in experimental colon cancer. Food Chem Toxicol 47:309–315PubMedCrossRefGoogle Scholar
  25. Khan R, Sultana S (2011) Farnesol attenuates 1,2-dimethylhydrazine induced oxidative stress, inflammation and apoptotic responses in the colon of Wistar rats. Chem Biol Interact 192:193–200PubMedCrossRefGoogle Scholar
  26. Kobuchi S et al (2011) Effect of oxidative stress on the pharmacokinetics of clomipramine in rats treated with ferric-nitrilotriacetate. Drug Metab Lett 5(4):243–252PubMedCrossRefGoogle Scholar
  27. Kobuchi S et al. (2012) Pharmacokinetics and distribution of fluvoxamine to the brain in rats under oxidative stress. Free Radic Res 46(7):831–841Google Scholar
  28. Kyowa Hakko Kirin Co., Ltd. (2011) 5-Fluorouracil (5-FU injection). [Drug Information]Google Scholar
  29. Kondo Y et al (2008) The Japanese journal of therapeutic drug monitoring. Jpn Soc Therap Drug Monit 25(3):167Google Scholar
  30. Labianca RF et al (2001) Disease management considerations: disease management considerations. Drugs 61:1751–1764PubMedCrossRefGoogle Scholar
  31. LaMont JT, O’Gorman TA (1978) Experimental colon cancer. Gastroenterology 75:1157–1169PubMedGoogle Scholar
  32. Li W, Li CB (2003) Lack of inhibitory effects of lactic acid bacteria on 1,2-dimethylhydrazine-induced colon tumors in rats. World J Gastroenterol 9:2469–2473PubMedGoogle Scholar
  33. Lowry OH et al (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193:265–275PubMedGoogle Scholar
  34. Lu Z et al (1998) Decreased dihydropyrimidine dehydrogenase activity in a population of patients with breast cancer: implication for 5-fluorouracil-based chemotherapy. Clin Cancer Res 4:325–329PubMedGoogle Scholar
  35. Macdonald JS, Astrow AB (2001) Adjuvant therapy of colon cancer. Semin Oncol 28:30–40PubMedCrossRefGoogle Scholar
  36. Matsushita R et al (2008) The 18th meeting of Japanese Society of pharmaceutical health care and sciences. Japanese Society of Pharmaceutical Health Care and Sciences, Tokyo, p 358Google Scholar
  37. Meropol NJ (1998) Oral fluoropyrimidines in the treatment of colorectal cancer. Eur J Cancer 34:1509–1513PubMedCrossRefGoogle Scholar
  38. Milano G, McLeod HL (2000) Can dihydropyrimidine dehydrogenase impact 5-fluorouracil-based treatment? Eur J Cancer 36:37–42PubMedCrossRefGoogle Scholar
  39. Milano G et al (1999a) Dihydropyrimidine dehydrogenase deficiency and fluorouracil-related toxicity. Br J Cancer 79:627–630PubMedCrossRefGoogle Scholar
  40. Milano G et al (1999b) Relationship between fluorouracil systemic exposure and tumor response and patient survival. J Clin Oncol 12(6):1291–1295Google Scholar
  41. Miyazaki K et al (2006) Influence of chemotherapeutic agents and cytokines on the expression of 5-fluorouracil-associated enzymes in human colon cancer cell lines. J Gastroenterol 41:140–150PubMedCrossRefGoogle Scholar
  42. Murray JF et al (1958) Circulatory changes in chronic liver disease. Am J Med 24:358–367PubMedCrossRefGoogle Scholar
  43. Nagai Y, Yoshiba M (1988) Studies on serum immunoreactive prolyl 4-hydroxylase in liver diseases–its elevation both in hepatocellular damage and cholestatic diseases. Clin Chim Acta 175:27–36PubMedCrossRefGoogle Scholar
  44. Nagata M et al (2010) Effect of acute hepatic failure on the hepatic first-pass effect of 5-fluorouracil in rats. J Pharm Pharmacol 62:598–603PubMedGoogle Scholar
  45. Naguib FN et al (1985) Enzymes of uracil catabolism in normal and neoplastic human tissues. Cancer Res 45:5405–5412PubMedGoogle Scholar
  46. Otsuka S et al (2005) Clinicopathological significance of pyrimidine nucleoside phosphorylase (PyNPase) and dihydropyrimidine dehydrogenase (DPD) in advanced colorectal cancer. Gan To Kagaku Ryoho 32(11):1679–1681PubMedGoogle Scholar
  47. Pegg AE (1978) Inhibition of the alkylation of nucleic acids and of the metabolism of 1,2-dimethylhydrazine by aminoacetonitrile. Chem Biol Interact 23(2):273–279PubMedCrossRefGoogle Scholar
  48. Pinedo HM, Peters GF (1988) Fluorouracil: biochemistry and pharmacology. J Clin Oncol 6:1653–1664PubMedGoogle Scholar
  49. Porsin B et al (2003) Dihydropyrimidine dehydrogenase circadian rhythm in mouse liver: comparison between enzyme activity and gene expression. Eur J Cancer 39:822–828PubMedCrossRefGoogle Scholar
  50. Rahman Z et al (2008) In vivo evaluation in rats of colon-specific microspheres containing 5-fluorouracil. J Pharm Pharmacol 60(5):615–623PubMedCrossRefGoogle Scholar
  51. Schmidt S et al (2010) Significance of protein binding in pharmacokinetics and pharmacodynamics. J Pharm Sci 99:1107–1122PubMedCrossRefGoogle Scholar
  52. Silva MF et al (2009) Effects of a probiotic soy product and physical exercise on formation of pre-neoplastic lesions in rat colons in a short-term model of carcinogenic. J Int Soc Sports Nutr 6:17PubMedCrossRefGoogle Scholar
  53. Sreedharan V et al (2009) Effect of morin on tissue lipid peroxidation and antioxidant status in 1,2-dimethylhydrazine induced experimental colon carcinogenesis. Invest New Drugs 27:21–30PubMedCrossRefGoogle Scholar
  54. Svobaite R et al (2008) HPLC with UV or mass spectrometric detection for quantifying endogenous uracil and dihydrouracil in human plasma. Clin Chem 54:1463–1472PubMedCrossRefGoogle Scholar
  55. Tateishi T et al (1996) Preliminary examination of the influence of incubation time or cytosolic protein concentration on dihydropyrimidine dehydrogenase activity. Clin Chim Acta 252:1–9PubMedCrossRefGoogle Scholar
  56. Tateishi T et al (1999) Dihydropyrimidine dehydrogenase activity and fluorouracil pharmacokinetics with liver damage induced by bile duct ligation in rats. Drug Metab Dispos Biol Fate Chem 27:651–654PubMedGoogle Scholar
  57. Twelves C et al (2005) Capecitabine as adjuvant treatment for stage III colon cancer. N Engl J Med 352(26):2696–2704PubMedCrossRefGoogle Scholar
  58. van Kuilenburg AB et al (2003) Pharmacogenetic and clinical aspects of dihydropyrimidine dehydrogenase deficiency. Ann Clin Biochem 40:41–45PubMedCrossRefGoogle Scholar
  59. van Kuilenburg AB et al (2012) Evaluation of 5-fluorouracil pharmacokinetics in cancer patients with a c.1905 + 1G > A mutation in DPYD by means of a Bayesian limited sampling strategy. Clin Pharmacokinet 51(3):163–174PubMedCrossRefGoogle Scholar
  60. Vella-Brincat JW et al (2007) Protein binding of cefazolin is saturable in vivo both between and within patients. Br J Clin Pharmacol 63:753–757PubMedCrossRefGoogle Scholar
  61. Yamashita S et al (1989) 5-Fluorouracil derivatives with serum protein binding potencies. Chem Pharm Bull (Tokyo) 37:2861–2863CrossRefGoogle Scholar
  62. Zhang R et al (1993) Relationship between circadian-dependent toxicity of 5-fluorodeoxyuridine and circadian rhythms of pyrimidine enzymes: possible relevance to fluoropyrimidine chemotherapy. Cancer Res 53:2816–2822PubMedGoogle Scholar

Copyright information

© Springer-Verlag France 2012

Authors and Affiliations

  • Shinji Kobuchi
    • 1
    Email author
  • Yukako Ito
    • 1
  • Kae Okada
    • 1
  • Kazuki Imoto
    • 1
  • Kanji Takada
    • 1
  1. 1.Department of PharmacokineticsKyoto Pharmaceutical UniversityKyotoJapan

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