Summary
Doxorubicin and 5-fluorouracil pharmacokinetics were studied in 19 volunteers with various advanced neoplastic diseases who received 50–90 mg doxorubicin or 600–1000 mg 5-fluorouracil intravenously, followed by plasma and parotid saliva collection over a 75 min period. The extent to which these chemotherapeutic agents are bound to plasma proteins, at concentrations chosen to approximate plasma concentrations, was measured by equilibrium dialysis. Both agents were quantitated by high-performance liquid chromatography. As reported previously, a wide range of plasma levels were found among patients receiving similar doses of either doxorubicin or 5-fluorouracil. It appears that in addition to being quickly cleared from the plasma both chemotherapeutic agents are excreted in detectable amounts in parotid saliva, a route of elimination heretofore given little or no attention. Excretion in the saliva exposes the mucosa of the upper gastrointestinal tract to 5-fluorouracil after intravenous administration and may play a part in causing stomatitis in patients receiving it by this route. Since there are huge interindividual and pronounced intraindividual differences in S/P ratios mostly not systematically related to the drugs' concentration in plasma, the concentration in parotid saliva was not useful in predicting the level of free doxorubicin or 5-fluorouracil in plasma.
Similar content being viewed by others
References
Abmersjo VE, Gustavsson BG, Regåralh CG, Wåhlen P (1980) Pharmacokinetic studies of 5-fluorouracil after oral and intravenous administration in man. Acta Pharmacol Toxicol (Copenh) 46 (5): 329–336
Anand C, Han SS (1975) Effects of 5-fluorouracil on exocrine glands. III. Fine structure of Brunner's glands of rats. J Anat 119: 1–19
Ansfield FJ, Schroeder JM, Curreri AR (1962) Five years clinical experience with 5-fluorouracil. J Am Med Assoc 181: 295–299
Bachur NR, Riggs CE, Langone JS Jr, Van Vunakis H, Levine L (1977) Plasma adriamycin and daunorubicin levels by fluorescence and radioimmunoassay. Clin Pharmacol Ther 21: 70–77
Baurain R, Deprez-De Campeneere D, Tronet A (1979) Rapid determination of doxorubicin and its fluorescent metabolites by high pressure liquid chromatography. Anal Biochem 94: 112–116
Benjamin RS, Wiernik PH, Bachur NR (1974) Adriamycin chemotherapy — efficiency, safety, and pharmacologic basis for an intermittent single high-dosage schedule. Cancer 33: 19–27
Carter SK (1975) Adriamycin — A review. J Natl Cancer Inst 55: 1265–1274
Christophidas N, Mihaly G, Vajda F, Louis W (1979) Comparison of liquid and gas-liquid chromatography assays of 5-fluorouracil in plasma. Clin Chem 25 (1): 83–86
Creaven PJ (1979) Pharmacokinetic parameters potential for and problems with their use as prediction of response to cancer chemotherapeutic agents. Bull Cancer (Paris) 66 (1): 85–88
DiGregorio GJ, Piraino AJ, Ruch E (1978) Correlation of parotid saliva and blood ethanol concentrations. Drug Alcohol Depend 3: 43–50
De Leenheer AP, Cosyns-Duyek MCl (1979) Flame-ionization glc assay for fluorouracil in plasma of cancer patients. J Pharm Sci 68: 1174–1176
Driessen O, De Vos D, Timmermans PJA (1979) Sensitive gasliquid chromatographic assay of underivatized 5-fluorouracil in plasma. J Chromatogr 162 (3): 451–456
Finn C, Sadée W (1975) Determination of 5-fluorouracil (NSC-19 893) plasma levels in rats and man by isotope dilution-mass fragmentography. Cancer Chemother Rep 59 (2 Pt 1): 279–286
Fraile RJ, Baker LH, Buroker TR, Horwitz J, Vaitkevicius VK (1980) Pharmacokinetics of 5-fluorouracil administered orally, by rapid intravenous and by slow infusion. Cancer Res 40: 2223–2228
Heidelberger C, Ansfield FJ (1963) Experimental and clinical use of fluorinated pyrimidines in cancer chemotherapy. Cancer Res 23: 1226–1243
Hillcoat BL, McCulloch BP, Figueredo AT, Ehsom MH, Rosenfield JM (1978) Clinical response and plasma levels of 5-fluorouracil in patients with colonic cancer treated by drug infusion. Br J Cancer 38: 719–724
Kaiwai M, Rosenfield J, McCulloch P, Hillcoat BL (1975) Letter: Blood levels of 5-fluorouracil during intravenous infusion. Cancer Chemother Rep 59 (2 Pt 1): 229–230
Kim MK, Han SS (1972) Effect of 5-fluorouracil on exocrine glands. I. Gland weights in mice receiving synthetic polynucleotides. Proceedings of the Society for Experimental Biology and Medicine 139: 1246–1251
Kuo JY, Shen HY, Wolfson P, Dreiling DA (1978) Effect of acute and chronic administration of 5-fluorouracil on pancreatic secretion. Am J Gastroenterol 70 (1): 89–93
Lakings DB, Adamson RH (1978) Quantitative analysis of 5-fluorouracil in human serum by selected ion monitoring gas chromatography-mass spectrometry. J Chromatogr 146: 512–517
Lee YN, Chan KK, Harris PA, Cohen JL (1980) Distribution of adriamycin in cancer patients. Cancer 45: 2231–2239
MacMillan WE, Wolberg WH, Welling PG (1978) Pharmacokinetics of fluorouracil in humans. Cancer Res 38: 3479–3482
Mukhejee KL, Currer AR, Javid M, Heidelberger L (1963) Studies on fluorinated pyrmidines XVI metabolism of 5-fluorinated 2-C14 and 5-fluoro-2′-deoxypyridine-2-C14 in cancer patients. Cancer Res. 23: 67–77
Reich SD, Steinberg F, Bachur NR, Riggs CE Jr, Goebel R, Berman M (1979) Mathematical model for adriamycin (doxorubicin) pharmacokinetics. Cancer Chemother Pharmacol 3: 125–131
Rollins DE, Klaasen CD (1979) Biliary excretion of drugs in man. Clin Pharmacokinet 4: 368–379
Sitar DS, Shaw DH Jr, Thirlwell MP, Ruedy JR (1977) Disposition of 5-fluorouracil after intravenous bolus doses of a commercial formulation of cancer patients. Cancer Res 37: 3981–3984
Wilkinson PM, Israel M, Pegg WJ, Frei E III (1979) Comparative metabolism and excretion of adriamycin in man, monkey and rat. Cancer Chemother Pharmacol 2: 121–125
Young RC, Ozoh RF, Myers CE (1981) The anthracycline antineoplastic drugs. N Engl J Med 305: 139–153
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Celio, L.A., DiGregorio, G.J., Ruch, E. et al. Doxorubicin and 5-fluorouracil plasma concentrations and detectability in parotid saliva. Eur J Clin Pharmacol 24, 261–266 (1983). https://doi.org/10.1007/BF00613829
Received:
Revised:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00613829