Summary
Plasma concentrations of 5-fluorouracil (FU) and its primary catabolite, 5′, 6′-dihydro-5-fluorouracil (DHFU) were measured using gas-liquid chromatography after single-dose therapy with 7.2–14.4 mg/kg. Because of the limited sensitivity of the assay for drug levels in plasma, the urinary excretion of FU and metabolites was investigated using an ion-specific electrode after either a single bolus (7.0–9.6 mg/kg) or multiple-dose therapy (6.4–7.4 mg/kg/day). Half-life values for the elimination of FU from plasma (mean, 123.5 min) were greater in each patient than for the catabolite (mean, 109.2 min). Values of the area under the curve for FU profiles varied between patients (mean±SE, 12.7±1.9 μg·h/ml) by comparison with the relatively constant values for curves of DHFU concentrations (mean±SE, 2.8±0.15 μg·h/ml). In pharmacokinetic profiles of urinary excretion a transient phase of convex shape was apparent after 80%–98% of single doses of FU was excreted. Half-lives for the elimination of FU in urine were 2.6–5.9 h, which increased to 18–44 h on multiple dosing. The results demonstrate saturation in the elimination of FU after therapeutic doses, and are consistent with the proposal that reduction of FU to DHFU provides the rate-limiting step.
Similar content being viewed by others
References
Ambre JJ, Fischer LJ (1971) The effect of prednisolone and other factors on the catabolism of 5-fluorouracil in rats. J Lab Clin Med 78:343–353
Calvert AH (1980) Pharmacokinetics of methotrexate and 5-fluorouracil. Cancer Topics 3:2–3
Cano JP, Rigault JP, Aubert C, Carcassonne Y, Seitz JF (1979) Determination of 5-fluorouracil in plasma by GC/MS using an internal standard. Applications to pharmacokinetics. Bull Cancer (Paris) 66:67–73
Chadwick M, Rogers WI (1972) The physiological disposition of 5-fluorouracil in mice bearing solid L1210 lymphocytic leukemia. Cancer Res 32:1045–1056
Christophidis N, Vajda FJE, Lucas I, Drummer O, Moon WJ, Louis WJ (1978) Fluorouracil therapy in patients with carcinoma of the large bowel: a pharmacokinetic comparison of various rates and routes of administration. Clin Pharmacokinet 3:330–336
Collins JM, Dedrick RL, King FG, Speyer JL, Myers CE (1980) Nonlinear pharmacokinetic models for 5-fluorouracil in man: intravenous and intraperitoneal routes. Clin Pharmacol Ther 28:235–246
Curry SH (1977) Drug disposition and pharmacokinetics: with a consideration of pharmacological and clinical relationship. Blackwell Scientific Publications, Oxford, p 155
Edelstyn GA, Bates TD, Brinkley D, MacRae KD, Spittle MF, Wheeler T (1975) Comparison of 5-day, 1-day and 2-day cyclical combination chemotherapy in advanced breast cancer. Lancet II:209–211
Edelstyn GA, Bates T, Brinkley D, MacRae KD, Spittle MF, Wheeler T (1977) Short-course cyclical chemotherapy in advanced breast cancer. Lancet I:592
Edelstyn GA, Bates T, Brinkley D, Evans RGB, Kitchen G, MacRae KD, Nichol NY, Spittle M, Wheeler T (1977) Multimodal therapy for histological stage II breast cancer. Lancet II:396–397
Finch RE, Bending MR, Lant AF (1979) Plasma levels of 5-fluorouracil after oral and intravenous administration in cancer patients. Br J Clin Pharmacol 7:613–617
Finn C, Sadee W (1975) Determination of 5-fluorouracil (NSC-19893) plasma levels in rats and man by isotope dilution-mass fragmentography. Cancer Chemother Rep 59:279–286
Garrett ER, Hurst GH, Green JR (1977) Kinetics and mechanisms of drug action on microorganisms. XXIII. Microbial kinetic assay for fluorouracil in biological fluids and its application to human pharmacokinetics. J Pharm Sci 66:1422–1429
Gibaldi M, Perrier D (1975) Pharmacokinetics. Marcel Dekker, New York
Kirkwood JM, Ensminger W, Rosowsky A, Papathanasopoulos N, Frei E III (1980) Comparison of pharmacokinetics of 5-fluorouracil and 5-fluorouracil, with concurrent thymidine infusions in a phase 1 trial. Cancer Res 40:107–113
McDermott BJ, van den Berg HW, Murphy RF (1979) Gas-liquid chromatographic analysis of 5-fluorouracil and its metabolite 5-fluorodihydrouracil in plasma. Biochem Soc Trans 7:65–66
McDermott BJ, van den Berg HW, Murphy RF (1980) Determination of 5-fluorouracil and metabolites in urine using an ion-specif c electrode technique. Irish J Med Sci 149:172
Metzler CM (1969) A user's manual for NONLIN. Upjohn Co., Kalamazoo (Technical Report no. 7292/69/7293/005)
Mukerjee KL, Boohar J, Wentland D, Ansfield FJ, Heidelberger C (1963) Studies in fluorinated pyrimidines. XVI. Metabolism of 5-fluorouracil-2-14C and 5-fluoro-2′-deoxyuridine-2-14C in cancer patients. Cancer Res 23:49–66
Myers CE (1981) The pharmacology of the fluoropyrimidines. Pharm Rev 33:1–15
Orion Research (1977) Instruction manual for fluoride electrodes. Orion Research, Cambridge (Mass.)
Russell TW, Duncan DM (1974) Catalytic reduction. III. Hydrogenation of unsaturated compounds over borohydride-reduced palladium. J Org Chem 39:3050–3052
Sitar DS, Shaw DH, Thirlwell MP, Ruedy JR (1977) Disposition of 5-fluorouracil after intravenous bolus doses of a commercial formulation to cancer patients. Cancer Res 37:3981–3984
Steyermark A, Kaup RR, Petras DA, Bass EA (1959) Microdetermination of fluorine in organic compounds following a modified Schoniger combustion. Microchem J 3:523–527
Venkateswarlu P (1975) Determination of total fluorine in serum and other biological materials by oxygen bomb and reverse extraction techniques. Anal Biochem 68:512–521
Venkateswarlu P (1975) A micromethod for direct determination of ionic fluoride in body fluids with the hanging drop fluoride electrode. Clin Chim Acta 59:277–282
van den Berg HW, Murphy RF, McDermott BJ (1978a) Pharmacokinetics of 5-fluorouracil. Br J Cancer 38:179–180
van den Berg HW, Murphy RF, Hunter R, Elmore DT (1978b) An improved gas-liquid chromatographic assay for 5-fluorouracil in plasma. J Chromatogr 145:311–314
Wagner JG (1963) Some possible errors in the plotting and interpretation of semilogarithmic plots of blood level and urinary excretion data. J Pharm Sci 52:1097–1101
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
McDermott, B.J., van den Berg, H.W. & Murphy, R.F. Nonlinear pharmacokinetics for the elimination of 5-fluorouracil after intravenous administration in cancer patients. Cancer Chemother. Pharmacol. 9, 173–178 (1982). https://doi.org/10.1007/BF00257748
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00257748