5-Fluorouracil pharmacokinetics

Terret C, Erdociain E, Guimbaud R et al. Dose and time dependencies of 5-fluorouracil pharmacokinetics. Clin Pharmacol Eher 2000 68 270-279. 

Khor SP, Amyx H, Davis ST, Nelson D, Baccanari DP, Spector T. Dihydropyrimidine dehydrogenase inactivation and 5-fluorouracil pharmacokinetics Allometric scaling of animal data, pharmacokinetics and toxicodynamics of 5-fluorouracil in humans. Cancer Chemother Pharmacol 1997 39 233-8. 

Maillart P, Allain YM, Minier JF, Dubin J. Toxicite cardiaque aigue du 5-fluorouracile correlation pharma-cocinetique. [Acute cardiac toxicity of 5-fluorouracil pharmacokinetic correlation.] Bull Cancer... 

One study suggested that intravenous dipyridamole may reduce the steady-state plasma levels of fluorouracil, whereas others found that oral dipyridamole caused no important changes in fluorouracil pharmacokinetics. 

Seymour MT, Patel N, Johnston A, Joel SP, SlevinML. Lack of effect of interferon a2a upon fluorouracil pharmacokinetics. Br J Cancer 99A) 70, 724-8. 

Gamelin E, Boisdron-Celle M, Guer-in-Meyer V et al. Correlation between uracil and dihydrouracil plasma ratio, fluorouracil (5-FU) pharmacokinetic parameters, and tolerance in patients with advanced colorectal cancer a potential interest for predicting 5-FU toxicity and determining optimal 5-FU dosage. J Clin Oncol 1999 17 1105-1110. 

Turning our attention first to alkyl carbamates of cyclic amides, we find interesting attempts to improve the pharmaceutical and pharmacokinetic properties of 5-fluorouracil (8.152, R = H) [194-196], This antitumor agent, while clinically useful, suffers from poor water solubility, unsatisfactory delivery properties and low tissue selectivity. A variety of prodrug candidates were prepared, in particular the alkyl and aryl carbamates presented in Table 8.12. With the exception of the more-lipophilic derivatives, these compounds exhibited somewhat improved water solubility. More importantly, both rectal and oral bioavailability were markedly improved. The activation... 

C.A. Present, W. Wolf, V. Waluch, C. Wiseman, P. Kennedy, D. Blayney, R.R. Brechner, Association of intratumoral pharmacokinetics of fluorouracil with clinical response. Lancet 343 (1994) 1184-1187. 

Heggie GD, Sommadossi IP, Cross DS et al. Clinical pharmacokinetics of 5-fluorouracil and its metabolites in plasma, urine, and bile. Cancer Res 1987 47 2203-2206. 

Bocci G, Barbara C, Vannozzi F et al. A pharmacokinetic-based test to prevent severe 5-fluorouracil... 

Bocci G, Danesi R, Allegrini G et al. Severe 5-fluorouracil toxicity associated with a marked alteration of pharmacokinetics of 5-fluorouracil and its catabolite 5-fluoro-5,6-dihydrouracil a case report. Eur J Clin Pharmacol 2002 58 593-595. 

Di Paolo A, Danes R, Ciofl L et al. Improved analysis of 5-fluorouracil and 5,6-dihydro-5-fluorouracil by HPLC with diode array detection for determination of cellular dihydropyrimidine dehydrogenase activity and pharmacokinetic profiling. Ther DrugMonit 2QQ5,21.362-36%. 

Bevacizumab, a humanized IgG and cetuximab, a chimeric IgGx, are currently marketed in the US for treatment of metastatic colorectal cancer [92, 93]. Bevacizumab neutralizes the biological activity of vascular endothelial growth factor (VEGF), while cetuximab binds specifically to the extracellular domain of the human epidermal growth factor receptor (EGFR). Bevacizumab, in combination with IV 5-fluorouracil (5-FU) -based chemotherapy, is indicated for first-line treatment of metastatic colorectal cancer, whereas cetuximab is used in patients refractory to or intolerant to irinotecan-based chemotherapy. The clinical pharmacokinetics of cetuximab are discussed in detail in Chapter 14. 

Pharmacokinetics Flucytosine is well absorbed by the oral route, distributes throughout the body water, and penetrates well into cerebrospinal fluid (CSF). 5-Fluorouracil is detectable in patients and probably is due to metabolism of 5-FC by intestinal bacteria. Excretion of both the parent drug and its metabolites is by glomerular filtration, and the dose must be adjusted in patients with compromised renal function. 

Gaudreault J, Shiu V, Bricarello A, Christian BJ, Zuch CL, Mounho B. Concomitant administration of bevacizumab, irinotecan, 5-fluorouracil, and leucovorin nonclin-cial safety and pharmacokinetics. Inti J Toxicol 2005 24 357-63. 

PET has already been applied to a wide number of drugs to demonstrate activity in vivo from standard chemotherapy such as 5-fluorouracil (5-FU). The pharmacokinetics of 5-FU has been successfully investigated using radiotracers, and is the most common anti-cancer drug imaged with PET (Kissel). This is due to the ease of chemical synthesis of 18F-fluorouracil... 

Harvey VJ, Slevin ML, Dilloway MR, Clark PI, Johnston A, Lant AF. The influence of cimetidine on the pharmacokinetics of 5-fluorouracil. Br J Clin Pharmacol 1984 18(3) 421-30. 

Jodrell Dl, Stewart M, Aird R, Knowles G, Bowman A, Wall L, Cummings J, McLean C. 5-fluorouracil steady state pharmacokinetics and outcome in patients receiving protracted venous infusion for advanced colorectal cancer. Br J Cancer 2001 84(5) 600-3. 

The pharmacokinetics of fluorouracil have been studied with escalating doses as a 72-hour intravenous infusion alone or in combination with a fixed dose of dipyridamole, a nucleoside transport inhibitor, and an enhancer of fluorouracil cytotoxicity (143). Stomatitis was dose-limiting at a fluorouracil dose of 2300 mg/m /day. For courses... 

Goldberg JA, Kerr DJ, Watson DG, Willmott N, Bates CD, McKillop JH, McArdle CS. The pharmacokinetics of 5-fluorouracil administered by arterial infusion in advanced colorectal hepatic metastases. Br J Cancer 1990 61(6) 913-15. 

Schuller J, Czejka M, Miksche M, et al. Influence of interferon alpha-2b leucovorin on pharmacokinetics of 5-fluorouracil. Proc Am Soc Clin Oncol 1991 10 98. 

Bardakji Z, Jolivet J, Langelier Y, Besner JG, Ayoub J. 5-Fluorouracil-metronidazole combination therapy in metastatic colorectal cancer. Clinical, pharmacokinetic and in vitro cytotoxicity studies. Cancer Chemother Pharmacol 1986 18(2) 140. ... 

Plasma levels of fluorouracil are erratic after oral dost High plasma levels are obtained after parenteral adniaor tion. but the pharmacokinetic characteristics are not liis-Fluorouracil is extensively metabolized in the liver, aajt main metabolite isdihydrofluorouracil. " Mostufanadin istered do.se is excreted in urine as o-fluoro- alanine... 

Wolf, W., Presant, C. A., Servis, K. L., et al. (1990) Tumor trapping of 5-fluorouracil in vivo I9F NMR spectroscopic pharmacokinetics in tumor-bearing humans and rabbits. Proceedings of the National Academy of Sciences U.S.A. 87(1), 492-496. 

Nicholls et al. have used NMR spectroscopy of urine combined with labelling with stable isotopes such as and to monitor the silent process of deacetylation and subsequent reacetylation (futile deactylation) in the rat as this has implications for the toxicity of paracetamoP and phenacetin. Hull et al. have monitored the metabolites of 5-fluorouracil in plasma and urine using NMR spectroscopy in patients receiving chemotherapy. Akira et al. have used H NMR to study the pharmacokinetics of benzoic... 

Several publications have demonstrated circadian variation in the pharmacokinetics and pharmacodynamics of 5-fluorouracil (5-FU) during constant infusions of varying rates typically infused over 5-14 days (55-57). The maximum and minimum concentrations each day based on cosinor analysis occurred at approximately 0100-0400 and 1300 hours, respectively. Dehydropyrimidine dehydrogenase (DPD) is primarily responsible for the metabolism of 5-FU and demonstrates circadian variation in activity with its maximum and minimum activity based on cosinor analysis occurring at 0100 and 1300 hours, respectively. Some patients demonstrated an inverse relationship to the plasma 5-FU concentration (55). This appeared to increase the tolerance to 5-FU side effects between OOOOh and 0400h (58, 59). 

G. Milano and A. L. Chamorey, Clinical pharmacokinetics of 5-fluorouracil with consideration of chronopharmacokinetics. Chronobiol Int 19 177-189 (2002). 

F. Bressolle, J. M. Joulia, F. Pinguet, M. Ychou, C. Astre, J. Duffour, and R. Gomeni, Circadian rhythm of 5-fluorouracil population pharmacokinetics in patients with metastatic colorectal cancer. Cancer Chemother Pharmacol 44 295-302 (1999). 

FAC may also be given with bolus doxorubicin administration, and the fluorouracil dose is then given on days 1 and 8. Paclitaxel may also be given concurrently with doxorubicin or epirubicin as a combination regimen. Pharmacokinetic interactions make these regimens more difficult to give. 

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