Abstract
The thymidine analogue (E)-5-(2-bromovinyl)-2′-deoxyuridine (BVdUrd), which is an antiviral agent effective against herpes simplex virus type 1 and varicella zoster virus, has also proved to be a potent inhibitor of dihydrouracil dehydrogenase, the major degrading enzyme of the anticancer drug fluorouracil (FUra). To evaluate the effect of BVdUrd on the pharmacokinetics of FUra in cancer patients, BVdUrd was administered orally at a daily dose of 250 mg (five patients) or 3×250 mg (five patients). FUra was infused at doses of 110–400 mg over 10 min. Blood and urine samples were collected regularly during a period of up to 50 h. BVdUrd was rapidly absorbed, peak plasma levels of 0.6–7.1 μg/ml being achieved after 1–2 h. Following a rapid decline, plasma BVdUrd levels remained higher than 10 ng/ml for up to 2 days after BVdUrd administration. The total body clearance of FUra was approximately 6 l/h andt 1/2 markedly increased to 4–7 h. The mean urinary excretion of FUra was 50%. No differences in FUra kinetics were observed between patients receiving one or three oral doses of BVdUrd. We conclude that the concomitant use and subsequent interaction of FUra and the antiviral agent BVdUrd resulted in an impressive inhibition of FUra breakdown and marked increase of renal clearance. The findings indicate that the simultaneous use of FUra and drugs resembling this antiviral agent in patients may result in unexpected toxicity. Further experience with BVdUrd and new analogues might enable the development of new FUra treatment schedules and treatment designs e.g. combinations with leucovorin.
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Abbreviations
- BVdUrd:
-
(E)-5-(2-bromovinyl)-2′-deoxyuridine
- FUra:
-
5-fluorouracil
- BVUra:
-
(E)-5-(2-bromovinyl)uracil
- C TB :
-
total body clearance
References
Abbruzzesse JL, Levin B (1989) Treatment of advanced colorec-tal cancer. Hematol/Oncol Clin North Am 3:135–152
Au Jl-S, Rustum YM, Ledesma EJ, Mittelman A, Creaven PJ (1982) Clinical pharmacological studies of concurrent colorectal carcinomas. Cancer Res 42:2930–2937
Buroker TR, Moertel CG, Fleming TR, Everson LK, Cullman SA, Krook JE, Maillard JA, Marschke RE, Klaassen DJ, Laurie JA, Moon MD (1985) A controlled evaluation of recent approaches to biochemical modulation or enhancement of 5-fluorouracil therapy in colorectal carcinoma. J Clin Oncol 3:1624–1631
De Bruijn EA, Remeyer L, Tjaden UR, Erkelens C, De Brauw LM, Van de Velde CJH (1986) Non-linear pharmacokinetics of 5-fluorouracil as described by behaviour of 5,6-dihydro-5-fluorouracil. Biochem Pharmacol 35:2461–2465
De Bruijn EA, Van Oosterom AT, Tjaden UR (1989) Site-specific delivery of fluorouracil with 5-deoxy-5-fluorouridine. Reg Cancer Treat 2:61–76
De Clercq E (1986) Potential of bromovinyldeoxyuridine in anticancer chemotherapyears Anticancer Res 6:549–556
De Clercq E, Descamps J, De Somer P, Barr PJ, Jones AS, Walker RT (1979) E-5-2-Bromovinyl-2′-deoxyuridine: a potent and selective antiherpes agent. Proc Natl Acad Sci USA 76:2947–2951
Desgranges C, Razaka G, De Clercq E, Herdewijn P, Balzarini J, Drouillet F, Bricaud H (1986) Effect of E-5-2-bromovinyluracil on the catabolism and antitumor activity of 5-fluorouracil in rats and leukemic mice. Cancer Res 46:1094–1101
Diasio RB, Beavers TL, Carpenter JT (1988) Familial deficiency of dihydropyrimidine dehydrogenase: biochemical basis for familial pyridinemia and severe 5-fluorouracil-induced toxicityears. J Clin Invest 81:47–51
Drewinko B, Yang LY (1985) Cellular basis for the inefficacy of 5-FU in human colon carcinoma. Cancer Treat Rep 6912:1391–1398
Iigo M, Yamaizumi Z, Nishimura S, Hoshi A, De Clercq E (1987) The antitumor potency of oral tegafur against adenocarcinoma 755 in mice is markedly enhanced by oral E-5-2-bromovinyl-2′-deoxyridine. Jpn J Cancer Res 78:409–413
Iigo M, Araki E, Nakajima Y, Hoshi A, De Clercq E (1988) Enhancing effect of bromovinyldeoxyuridine on antitumor activity of 5-fluorouracil against adenomacarcinoma 755 in mice. Increased therapeutic index and correlation with increased plasma 5-fluorouracil levels. Biochem Pharmacol 37:1609–1613
Iigo M, Nishikata KI, Nakajima Y, Hoshi A, De Clercq E (1990) Effect on E-5-2-bromovinyl-2′-deoxyridine on life-span and 5-fluorouracil metabolism in mice with hepatic metastases. Eur J Cancer 26:1089–1092
Keizer HJ, Pauwels R, Landuyt W, Balzarini J, Van der Schueren E, De Clercq E (1988) Combined effects of bromovinyldeoxyridine and fractionated or continuous administration of 5-fluorouracil in P388 leukemia-bearing mice. Cancer Letters 39:217–223
Kirkwood JM, Ensminger W, Rosowsky A, Papathanasopolous N, Frei III E (1980) Comparison of pharmacokinetics of 5-fluorouracil with concurrent thymidine infusions in a phase-I trial. Cancer Res 40:107–113
Kish JA, Ensley JF, Jacobs J, Weaver A, Cummings G, Al-Sarraf HA (1985) A randomized trial of cisplatin+5-fluorouracil bolus for recurrent and advanced squamous cell carcinoma of the head and neck. Cancer 56:2740–2744
Martin DS, Stolfi RL, Swayer RC, Rabindranath N, Spiegelman S, Young CW, Woodcock T (1980) An overview of thymidine. Cancer 45:1117–1128
Milano G, Etienne MC, Cassuto-Viguier E, Thyss A, Santini J, Freany M, Renee N, Schneider M, Demard F (1992) Influence of sex and age on fluorouracil clearance. J Clin Oncol 10:1171–1175
Moertel CG, Fleming TR, MacDonald JS, Haller DG, Laurie JA, Goodman PJ, Uungerleider JS, Emerson WA, Tormey DC, Glick JH, Veeder MH, Mailliard JA (1990) Levamisole and fluorouracil for adjuvant therapy of resected colon carcinoma. N Engl J Med 11:352–358
Pinedo HM, Peters GFJ (1988) Fluorouracil: biochemistry and pharmacology. J Clin Oncol 6:1653–1664
Reeuwijk HJEM, Lingeman H, Tjaden UR, De Bruijn EA, Keizer HJ, Van der Greef J (1988) Bioanalysis of E-5-2-bromocovinyl-2′-deoxyuridine. J Chromotagr 428:93–102
Tjaden UR, Lingeman H, Reeuwijk HJEM, De Bruijn EA, Keizer HJ, Van der Greef J (1988) Bioanalysis of 5-fluorouracil applying liquid chromatography and valve switching. Chromatographia 25:806–810
Tuchman M, Ramnaraine MLR, O'Dea RF (1985) Effects of uridine and thymidine on the degradation of 5-fluorouracil, uracil and thymine by rat liver dehydropyrimidine dehydrogenase. Cancer Res 45:5553–5556
Vogel SJ, Presant CA, Ratkin GA, Klahr C (1979) Phase-I study of thymidine plus 5-fluorouracil infusions in advanced colorectal carcinoma. Cancer Treat Rep 63:1–5
Vogelzang NJ (1984) Continuous infusion Chemotherapy: A critical review. J Clin Oncol 2:1289–1303
Wildiers J, De Clercq E (1984) Oral (E)-5-(2-bromovinyl)-2′-deoxyuridine treatment of severe herpes zoster in cancer patients. Eur J Cancer Clin Oncol 20:471–476
Woodcock TM, Martin DS, Damin Lam, Kemeny NE, Young CW (1980) Combination clinical trials with thymidine and fluorouracil: a phase-I and clinical pharmacologic evaluation. Cancer 45:1135–1143
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Keizer, H.J., De Bruijn, E.A., Tjaden, U.R. et al. Inhibition of fluorouracil catabolism in cancer patients by the antiviral agent (E)-5-(2-bromovinyl)-2′-deoxyuridine. J Cancer Res Clin Oncol 120, 545–549 (1994). https://doi.org/10.1007/BF01221032
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DOI: https://doi.org/10.1007/BF01221032