Fluorouracil (5FU) Pharmacokinetics in 5FU Prodrug Formulations With a Dihydropyrimidine Dehydrogenase Inhibitor (2001)

Article Tools SPECIAL DEPARTMENTS Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/JCO.2001.19.22.4267 Journal of Clinical Oncology - published online before print September 21, 2016 PMID: 11709571 Fluorouracil (5FU) Pharmacokinetics in 5FU Prodrug Formulations With a Dihydropyrimidine Dehydrogenase Inhibitor G. J. PetersxG. J. PetersSearch for articles by this author , C. J. van GroeningenxC. J. van GroeningenSearch for articles by this author , G. GiacconexG. GiacconeSearch for articles by this author Robert M. White JrxRobert M. White JrSearch for articles by this author Show More Vrije Universiteit Medical Center, Amsterdam, the NetherlandsFood and Drug Administration, Rockville, MD https://doi.org/10.1200/JCO.2001.19.22.4267 First Page Full Text PDF Figures and Tables © 2001 by American Society of Clinical OncologyjcoJ Clin OncolJournal of Clinical OncologyJCO0732-183X1527-7755American Society of Clinical OncologyResponse15112001In Reply:My reply reiterates the key issue, identifies differences with Drs Peters, van Groeningen, and Giaccone’s letter and the published literature, and articulates what I believe is the scientific remedy.First, in their original article, van Groeningen et al1 made the point that prolongation of the half-life of 5-fluorouracil (5FU) after S-1 (ftorafur [FT] or tegafur, 5-chloro-2,4-dihydroxypyridine [CDHP], and potassium oxonate) was evidence of reversible inhibition of dihydropyrimidine dehydrogenase (DPD) in vivo by CDHP.1 The reported prolonged half-life of 5FU after oral administration of S-1 was 3 to 4 hours. The fluoropyrimidine they compared with oral S-1 was intravenous-injection 5FU. I stated that the 5FU half-life after a short intravenous injection of 5FU was not the correct comparator. Because the source of 5FU in S-1 was the 5FU prodrug, tegafur, the correct comparator is the 5FU half-life after administration of oral tegafur.2 In their response to criticism of their pharmacokinetic evaluation of 5FU after S-1, Peters, van Groeningen, and Giaccone (the authors) acknowledged that comparison to the 5FU half-life after tegafur was “formally correct.”Second, the authors stated that the initial half-life of 5FU after intravenous tegafur was 10 minutes. They claimed that this was similar to the half-life of 5FU given intravenously and orally. Later, they stated that the 5FU mean residence time, a parameter which gave more information about oral formulations than half-life, was 4 hours for tegafur and 6 hours for S-1. The 5FU half-life (measured in minutes) and 5FU mean residence time (measured in hours) after tegafur were not consistent. Previously, Pinedo and Peters3 reported consistent 5FU beta half-lives and 5FU mean residence times (10 to 20 minutes and 12 to 23 minutes, respectively) after intravenous bolus 5FU. In their original article, 5FU half-lives and 5FU mean residence times after S-1 were not different by an order of magnitude.1 Until a tegafur study is conducted that calculates 5FU half-life and 5FU mean residence time from the same data set, the divergence of 5FU half-life and mean residence time after tegafur, as described by the authors, should be viewed with caution.The 5FU half-life after tegafur, which the authors cited, was also not consistent with results reported from non-English publications. In the German literature, Schüller et al4 stated that the 5FU half-life after oral tegafur was 54 minutes. In the Russian literature (tegafur or ftorafur was discovered in the former Soviet Union), the 5FU half-life after tegafur (route of administration was not specified) was approximately 5 hours.5 Note that, from Russian investigators, the 5FU half-life (5 hours) and 5FU mean residence time (4 hours) after tegafur were not different by an order of magnitude.6 However, it is unknown whether the two parameters were derived from the same data set. In view of the different analytical methodologies used to evaluate the 5FU pharmacokinetics in the historical literature, all that can be concluded is that cross-study comparisons are not reliable in this case.From unpublished data, the authors reported that the 5FU half-life after uracil plus tegafur (UFT) was 40 minutes. This is in stark contrast to the published reports, which have reported (1) apparent beta half-lives of 5FU after UFT of 5.2 and 7.2 hours at days 1 and 5, respectively,7 and (2) terminal half-lives of 5FU after UFT of 3.4 and 3.2 hours for fasted and fed treatments, respectively.8 The former published results were reported in review articles about UFT.9,10 Interestingly, Hirata et al11 cited the alpha-phase half-life of 5FU after UFT (20 minutes) from the article by Ho et al7 and not the beta-phase half-life of 5FU. This fits with Hirata et al’s argument that DPD inhibitory activity, as it affects 5FU half-life, increased in the following order: intravenous 5FU, UFT, S-1, and ethynyluracil/5FU (not a 5FU prodrug combination). This is reasoning similar to that of the authors. Based on the available information in the literature which was not cited by the authors or Hirata et al, this argument is not as straightforward if the beta-phase (elimination) half-lives of 5FU after UFT and tegafur are used.Finally, the only conclusion that can be drawn from the response of the authors is that a prospective, direct, pharmacokinetic study of oral S-1 and oral tegafur should be conducted. This is consistent with a commonly accepted scientific principle of selection of an appropriate control for an experiment. Intravenous 5FU is not the correct control for comparison to a tegafur combination for a number of reasons. First, in the case of intravenous 5FU, 5FU is the immediately available, active drug and is subject only to 5FU elimination. Second, 5FU derived from oral tegafur, the fluoropyrimidine component of S-1, is additionally subject to absorption of tegafur and formation of 5FU from tegafur. Third, because 5FU clearance should be the same with intravenous 5FU and oral tegafur, a change in 5FU volume of distribution may account for a change in 5FU half-life after tegafur and without any effect on DPD (recall that half-life is proportional to volume of distribution and inversely proportional to clearance). The authors’ cross-study comparisons are not convincing that the potency of DPD inhibition explains completely 5FU pharmacokinetics when DPD inhibitors are combined with tegafur. Depending on which historical tegafur data one uses—5FU half-life or 5FU mean residence time—in evaluating these DPD inhibitor–tegafur formulations, the possible change in 5FU pharmacokinetics ranges from small to large. Science calls for a prospective, comparative study of S-1 versus tegafur. The views expressed herein do not necessarily represent the views or findings of the United States Food and Drug Administration or the United States government. 1. van Groeningen CJ, Peters GJ, Schornagel JH, et al: Phase I clinical and pharmacokinetic study of oral S-1 in patients with advanced solid tumors. J Clin Oncol 18:: 2772,2000-2779, Link, Google Scholar2. White RM: Correct fluorouracil (5-FU) half-life comparator for a 5-FU prodrug plus a dihydropyrimidine dehydrogenase inhibitor. J Clin Oncol 19:: 2970,,2001 (letter) Link, Google Scholar3. Pinedo HM, Peters GF: Fluorouracil: Biochemistry and pharmacology. J Clin Oncol 6:: 1653,1988-1664, Link, Google Scholar4. Schüller J, Czejka MJ, Jäger W, et al: Comparative bioavailability of fluorouracil and its prodrug, ftorafur, following intra-arterial, intravenous and preoral administration (in German). Pharmazie 46:: 587,1991-588, Medline, Google Scholar5. 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