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© 2001 American Society for Clinical Oncology
Fluorouracil (5FU) Pharmacokinetics in 5FU Prodrug Formulations With a Dihydropyrimidine Dehydrogenase InhibitorVrije Universiteit Medical Center, Amsterdam, the Netherlands To the Editor:White1 criticized our pharmacokinetic evaluation of 5-fluorouracil (5FU) when administered as the S-1 formulation2 and suggested that we should have compared the half-life of 5FU with that of 5FU derived from single-agent tegafur. S-1 is a mixture of the 5FU prodrug tegafur, the dihydropyrimidine dehydrogenase (DPD) inhibitor 5-chloro-2,4-dihydroxypyridine (CDHP), and the phosphoribosyltransferase inhibitor, oxonic acid. Oxonic acid accumulates selectively in the gut,3 where it inhibits the conversion of 5FU to 5-fluorouridine 5'-monophosphate, a precursor for 5-fluoro-2'-deoxyuridine-5'-monophosphate, the active metabolite of 5FU, which inhibits the target enzyme thymidylate synthase.4 Since oxonic acid does not accumulate in the tumor,3 it has a selective protective effect against gastrointestinal toxicity but does not affect the antitumor activity. Oxonic acid does not affect the pharmacokinetics of 5FU. DPD catalyzes the degradation of 5FU, which is responsible for more than 80% of its elimination. CDHP is a very potent competitive inhibitor of DPD (inhibition constant, 0.36 µM), which is much more potent than the natural substrate uracil,5 which also competitively inhibits 5FU degradation (inhibition constant, 9 µM).6 The formulation of UFT consists of tegafur and uracil in a molar ratio of 1:4, respectively.7 UFT is registered in Japan and several European countries for palliative treatment of colon cancer. S-1 is currently under evaluation for its efficacy against colon and gastric cancer in Europe, but it has been registered in Japan for treatment of gastric cancer and head and neck cancer. In addition to UFT and S-1, the combination of ethynyluracil (EU) and 5FU is currently being investigated.8 EU is more potent than CDHP and is a so-called suicide inhibitor of DPD.9 EU irreversibly inactivates DPD; therefore, DPD activity can recover only by new enzyme synthesis. White1 suggested that in the S-1 formulation, we should have compared the pharmacokinetics of 5FU with that of 5FU derived from tegafur. The uptake and elimination of 5FU derived from tegafur are determined by a number of different parameters. First, after oral intake of S-1 (at 40 mg/m2), tegafur has to be absorbed from the gastrointestinal tract, which results in a peak of 9.5 µM at approximately 100 min (Peters et al, manuscript in preparation),10 after which tegafur is rapidly distributed. Tegafur has a half-life elimination of approximately 400 min. Subsequently, it has to be cleaved to 5FU, for which the cytochrome P450 isozyme CYP 2A6 is partially responsible.11 This enzyme is widely distributed in whites.11,12 The fate of 5FU is determined by its distribution and elimination. The latter process is influenced by the extent of inhibition of 5FU degradation by DPD; the more potent this inhibition, the longer the retention of 5FU in plasma. So, theoretically, one would expect a relatively short half-life of 5FU derived from tegafur in the UFT combination compared with that in the S-1 combination. This was indeed found, as illustrated in Fig. 1, which shows the 5FU pharmacokinetics of 5FU derived from either UFT or S-1, with half-lives of 40 minutes and 2 to 4 hours, respectively. Because EU is a more potent inhibitor of DPD, one would expect an even longer elimination of 5FU, which was indeed more than 6 hours despite the fact that, in this formulation, 5FU itself was given and not tegafur.8,13 Also, the peak concentration of 5FU was higher in the 5FU-EU combination. The initial half-life of 5FU derived from tegafur, when given as an intravenous infusion, is 10 minutes.14 This 10-minute half-life is comparable to that of 5FU given as an intravenous infusion15 and orally,16 but it is significantly shorter than that with each DPD inhibitor, including the relatively weak DPD inhibitor uracil. Thus, it can be concluded that the increased half-life of 5FU derived from UFT is due to the inhibition of DPD. In addition, the pharmacokinetics of 5FU derived from oral tegafur given as a single agent, compared with that with uracil (UFT formulation) and CDHP (S-1 formulation), are clearly different. Although the area under the curve of tegafur at 800 mg/m2(ref 17) was much higher than that after UFT (tegafur at 300-400 mg/m2) or S-1 (tegafur at 40 mg/m2), the area under the curve and maximum concentration of 5FU were higher in the formulations compared with tegafur alone. In addition, the mean residence time for 5FU, which gives more information on these oral formulations than the half-life, was longer in S-1 (6 hours) than that of 5FU derived from single oral tegafur (4 hours). Thus, it can be concluded that the increasing difference in the S-1 formulation and EU-5FU seems to be related to the increasing potency of the DPD inhibitor. When considering the fact that in the EU-5FU combination 5FU itself is given, one can conclude that the increase in the half-life and mean residence time in oral 5FU formulations with a DPD inhibitor is due mainly to the potency of the DPD inhibitor.
White1 states that the half-lives of 5FU derived from the S-1 and UFT formulations should be compared with the half-life of 5FU derived from tegafur as a single agent. Although formally correct, the data strongly indicate that 5FU pharmacokinetics from each oral formulation are predominantly determined by the potency of the DPD inhibitor. In case each separate constituent of a formulation is not toxic, the formulation should be considered as one drug. The pharmacokinetics of the other constituent of UFT, uracil, has been investigated extensively, as it is the breakdown product of uridine. Uridine administered as a 1-hour intravenous infusion to patients resulted in plasma uracil levels of up to 0.3 mM,18 which was eliminated with a terminal half-life of 40 minutes, with no toxicity. Uracil levels after UFT administration are approximately 0.1 mM.19 In contrast, uracil levels after S-1 administration increase from approximately 0.1 µM to 10 µM, which clearly demonstrates an effect of DPD inhibition. Also, after oral uridine administration, uracil levels up to 100 µM were not associated with toxicity.20 Therefore, in our view, each oral formulation with a DPD inhibitor should be considered as a separate drug, with properties, including pharmacokinetics, specific for that drug. REFERENCES
1.
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)
2.
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: 2772-2779, 2000
3.
Shirasaka T, Nakano K, Takechi T, et al: Antitumor activity of 1 M tegafur-0.4 M 5-chloro-2,4-dihydroxypyridine-1 M potassium oxonate (S-1) against human colon carcinoma orthotopically implanted into nude rats. Cancer Res 56: 2602-2606, 1996 4. Peters GJ, Köhne CH: Fluoropyrimidines as antifolate drugs, in Jackman AL (ed): Antifolate Drugs in Cancer Therapy. Totowa, NJ, Humana Press, 1999, pp 101-145 5. Tatsumi K, Fukushima M, Shirasaka T, et al: Inhibitory effects of pyrimidine, barbituric acid and pyridine derivatives on 5-fluorouracil degradation in rat liver extracts. Jpn J Cancer Res 78: 748-755, 1987[Medline] 6. Naguib FN, el Kouni MH, Cha S: Structure-activity relationship of ligands of dihydrouracil dehydrogenase from mouse liver. Biochem Pharmacol 38: 1471-1480, 1989[Medline] 7. Hoff PM, Pazdur R, Benner SE, et al: UFT and leucovorin: A review of its clinical development and therapeutic potential in the oral treatment of cancer. Anticancer Drugs 9: 479-490, 1998[Medline]
8.
Schilsky RL, Hohneker J, Ratain MJ, et al: Phase I clinical and pharmacologic study of eniluracil plus fluorouracil in patients with advanced cancer. J Clin Oncol 16: 1450-1457, 1998
9.
Porter DJ, Chestnut WG, Merrill BM, et al: Mechanism-based inactivation of dihydropyrimidine dehydrogenase by 5-ethynyluracil. J Biol Chem 267: 5236-5242, 1992
10.
Hirata K, Horikoshi N, Aiba K, et al: Pharmacokinetic study of S-1, a novel oral fluorouracil antitumor drug. Clin Cancer Res 5: 2000-2005, 1999
11.
Komatsu T, Yamazaki H, Shimada N, et al: Involvement of microsomal cytochrome P450 and cytosolic thymidine phosphorylase in 5-fluorouracil formation from tegafur in human liver. Clin Cancer Res 7: 675-681, 2001 12. Shimada T, Yamazaki H, Guengerich FP: Ethnic-related differences in coumarin 7-hydroxylation activities catalyzed by cytochrome P4502A6 in liver microsomes of Japanese and Caucasian populations. Xenobiotica 26: 395-403, 1996[Medline] 13. Baker SD, Khor SP, Adjei AA, et al: Pharmacokinetic, oral bioavailability, and safety study of fluorouracil in patients treated with 776C85, an inactivator of dihydropyrimidine dehydrogenase. J Clin Oncol 14: 3085-3096, 1996[Abstract]
14.
Au JL, Sadee W: 5-Fluorouracil concentrations in human plasma following R,S-1-(tetrahydro-2-furanyl)-5-fluorouracil (ftorafur) administration. Cancer Res 39: 4289-4290, 1979 (letter)
15.
van Groeningen CJ, Pinedo HM, Heddes J, et al: Pharmacokinetics of 5-fluorouracil assessed with a sensitive mass spectrometric method in patients on a dose escalation schedule. Cancer Res 48: 6956-6961, 1988 16. Abernethy DR, Alper JC, Wiemann MC, et al: Oral 5-fluorouracil in psoriasis: Pharmacokinetic-pharmacodynamic relationships. Pharmacology 39: 78-88, 1989[Medline] 17. Manzuik LV, Perevodchikova NI, Gorbunova VA, et al: Initial clinical experience with oral ftorafur and oral 6R,S leucovorin in advanced colorectal carcinoma. Eur J Cancer 29A: 1793-1794, 1993 (letter)
18.
Leyva A, van Groeningen CJ, Kraal I, et al: Phase I and pharmacokinetic studies of high-dose uridine intended for rescue from 5-fluorouracil toxicity. Cancer Res 44: 5928-5933, 1984 19. Ho DH, Pazdur R, Covington W, et al: Comparison of 5-fluorouracil pharmacokinetics in patients receiving continuous 5-fluorouracil infusion and oral uracil plus N1-(2’-tetrahydrofuryl)-5-fluorouracil. Clin Cancer Res 4: 2085-2088, 1998[Abstract]
20.
van Groeningen CJ, Peters GJ, Nadal JC, et al: Clinical and pharmacologic study of orally administered uridine. J Natl Cancer Inst 83: 437-441, 1991
ResponseFood and Drug Administration, Rockville, MD In 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.
NOTES 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. REFERENCES 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: 2772-2779, 2000 2. 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)
3.
Pinedo HM, Peters GF: Fluorouracil: Biochemistry and pharmacology. J Clin Oncol 6: 1653-1664, 1988 4. 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: 587-588, 1991[Medline] 5. Perevodchikova NI : Protivoopukholevaia khimioterapiia: Spra-vochnik/pod redaktsiei Perevodchikovoi [Reference Book for Antineoplastic Chemotherapy]. Moskva, Russia, Meditsina, 1993, p 15 6. Manzuik LV, Perevodchikova NI, Gorbunova VA, et al: Initial clinical experience with oral ftorafur and oral 6R,S leucovorin in advanced colorectal carcinoma. Eur J Cancer 29A: 1793-1794, 1993 (letter) 7. Ho DH, Pazdur R, Covington W, et al: Comparison of 5-fluorouracil pharmacokinetics in patients receiving continuous 5-fluorouracil infusion and oral uracil plus N1-(2’-tetrahydrofuryl)-5-fluorouracil. Clin Cancer Res 4: 2085-2088, 1998
8.
Damle B, Ravandi F, Kaul S, et al: Effect of food on the oral bioavailability of UFT and leucovorin in cancer patients. Clin Cancer Res 7: 517-523, 2001 9. Hoff PM, Pazdur R, Benner SE, et al: UFT and leucovorin: A review of its clinical development and therapeutic potential in the oral treatment of cancer. Anticancer Drugs 9: 479-490, 1998
10.
Hoff PM, Pazdur R: UFT plus oral leucovorin: A new oral treatment for colorectal cancer. The Oncologist 3: 155-164, 1998 11. Hirata K, Horikoshi N, Aiba K, et al: Pharmacokinetic study of S-1, a novel oral fluorouracil antitumor drug. Clin Cancer Res 5: 2000-2005, 1999
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Copyright © 2001 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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). Plasma concentrations from UFT and S-1 are partly from van Groeningen et al
