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Clinical Pharmacokinetics

, Volume 20, Issue 2, pp 99–113 | Cite as

Clinical Pharmacokinetics of Epoetin (Recombinant Human Erythropoietin)

  • Iain C. Macdougall
  • David E. Roberts
  • Gerald A. Coles
  • John D. Williams
Drug Disposition

Summary

Epoetin (recombinant human erythropoietin, EPO) is of proven benefit in the treatment of renal anaemia, and preliminary reports suggest that it may have a role in the management of other anaemic conditions. Pharmacokinetic and therapeutic studies have examined the use of epoetin administered intravenously, intraperitoneally and subcutaneously, and there is accumulating evidence that the last route has several advantages. After intravenous administration, epoetin is distributed in a volume comparable to the plasma volume, and plasma concentrations decay monoexponentially with a half-life of between 4 and 12 hours. Administration of epoetin in peritoneal dialysis fluid results in detectable concentrations in the bloodstream after 1 to 2 hours, and peak concentrations of the order of 2 to 4% of those obtained with the same intravenous dose are found after approximately 12 hours. The bioavailability of epoetin administered intraperitoneally in dialysis fluid is about 3 to 8%, but this may be increased by injecting the drug into a dry peritoneal cavity. Subcutaneous administration results in peak concentrations at about 18 hours which are 5 to 10% of those found after the same intravenous dose. The bioavailability of subcutaneous epoetin is about 20 to 30%, and detectable serum concentrations are still present 4 days after administration, in contrast to intravenous administration after which concentrations have returned to baseline within 2 to 3 days.

Remarkably little is known about the metabolic fate of either erythropoietin or epoetin. In addition, there is much controversy surrounding the relative roles of the kidney and liver in the catabolism of epoetin. About 3 to 10% of epoetin is excreted unchanged in the urine. In common with other glycoproteins, the carbohydrate residues which constitute 40% of its molecular size are essential for maintaining the stability of epoetin in circulation. Desialated epoetin, although biologically active in vitro, is cleared very rapidly from plasma with resultant loss of activity. Further work is required, however, in identifying the pathways of metabolism and elimination of this glycoprotein hormone.

Keywords

Erythropoietin Haemodialysis Patient Recombinant Human Erythropoietin Glycoprotein Hormone Renal Anaemia 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. Abbrecht PH, Litteil JK. Plasma erythropoietin in men and mice during acclimatisation to different altitudes. Journal of Applied Physiology 32: 54–58, 1972PubMedGoogle Scholar
  2. Al-khatti A, Veith RW, Papayannopoulou T, Fritsch EF, Gold-wasser E. et al. Stimulation of fetal hemoglobin synthesis by erythropoietin in baboons. New England Journal of Medicine 317: 415–420, 1987PubMedCrossRefGoogle Scholar
  3. Anagnostou A. Erythropoietin: a hematopoietic hormone produced by the kidney. Seminars in Nephrology 5: 104–114, 1985PubMedGoogle Scholar
  4. Annable L, Cotes PM, Müssen MV. The second international reference preparation of erythropoietin, human, urinary, for bioassay. Bulletin Organization Monde Santé 47: 99–112, 1972Google Scholar
  5. Bargman JM, Breborowicz A, Rodela H, Sombolos K, Oreopoulos DG. Intraperitoneal administration of recombinant human erythropoietin in uremic animals. Peritoneal Dialysis International 8: 249–252, 1988Google Scholar
  6. Birgegard G, Hallgren R, Caro J. Serum erythropoietin in rheumatoid arthritis and other inflammatory arthritides: relationship to anaemia and the effect of anti-inflammatory treatment. British Journal of Haematology 65: 479–483, 1987PubMedCrossRefGoogle Scholar
  7. Birgegard G, Miller O, Caro J, Erslev AJ. Serum erythropoietin levels by radioimmunoassay in polycythaemia. Scandinavian Journal of Haematology 29: 161–167, 1982PubMedCrossRefGoogle Scholar
  8. Boelaert JR, Schurgers ML, Matthys EG, Belpaire FM, Daneels RF, et al. Comparative pharmacokinetics of recombinant erythropoietin administered by the intravenous, subcutaneous and intraperitoneal routes in continuous ambulatory peritoneal dialysis patients. Peritoneal Dialysis International 9: 95–98, 1989PubMedGoogle Scholar
  9. Bommer J, Alexiou U, Muller-Buhl E, Eifert J, Ritz E. Recombinant human erythropoietin therapy in haemodialysis patients — dose determination and clinical experience. Nephrology, Dialysis, Transplantation 2: 238–242, 1987PubMedGoogle Scholar
  10. Bommer J, Ritz E, Weinreich T, Bommer G, Ziegler T. Subcutaneous erythropoietin. Lancet 2: 406, 1988PubMedCrossRefGoogle Scholar
  11. Caro J, Brown S, Miller O, Murray T, Erslev AJ, Erythropoietin levels in uremic nephric and anephric patients. Journal of Laboratory and Clinical Medicine 93: 449–458, 1979PubMedGoogle Scholar
  12. Caro J, Erslev AJ, Erythropoietin assays and their use in the study of anemias. Contributions to Nephrology 66: 54–62, 1988PubMedGoogle Scholar
  13. Casati S, Passerini P, Campise MR, Graziani G, Cesana B, et al. Benefits and risks of protracted treatment with human recombinant erythropoietin in patients having haemodialysis. British Medical Journal 295: 1017–1020, 1987PubMedCrossRefGoogle Scholar
  14. Cotes PM, Pippard MJ, Reid CDL, Winearls CG, Oliver DO, et al. Characterization of the anaemia of chronic renal failure and the mode of ils correction by a preparation of human erythropoietin (r-Hu EPO): an investigation of the pharmacokinetics of intravenous erythropoietin and its effects on erythro-kinetics. Quarterly Journal of Medicine 262: 113–137, 1989Google Scholar
  15. Danielson BG. Pharmacokinetics of intravenous and subcutaneous human recombinant erythropoietin in healthy volunteers Abstract. 2nd Investigators’ Meeting on R-hu EPO, Vienna, p. 3. 1988Google Scholar
  16. Davis JM, Arakawa T, Strickland TW, Yphantis DA. Characterization of recombinant human erythropoietin produced in Chinese hamster ovary cells. Biochemistry 26: 2633–2638, 1987PubMedCrossRefGoogle Scholar
  17. Dinkelaar RB, Engels EY, Hart AAM, Schoemaker LP, Bosch E. et al. Metabolic studies on erythropoietin (Ep): II. The role of liver and kidney in the metabolism of Ep. Experimental Haematology 9: 796–803, 1981Google Scholar
  18. Dunn CDR, Lange RD. Erythropoietin: assay and characterization: In Roath (Ed.) Topical reviews in hematology, pp. 1–32. Wright, Bristol. 1980Google Scholar
  19. Egrie JC, Browne JK, Lai P, Lin FK. Characterization and biological effects of recombinant human erythropoietin. Immu-nobiology 172: 213–224, 1986Google Scholar
  20. Egrie JC, Eschbach JW, McGuire T, Adamson JW. Pharmacokinetics of recombinant human erythropoietin administered to hemodialysis patients. Kidney International 33: 262. 1988Google Scholar
  21. Elliott S, Delorme E, Talbot C, Chang D, Hesterberg L. Characterization of anti-erythropoietin monoclonal antibodies. Blood 74(Suppl): 1228. 1989Google Scholar
  22. Emanucle RM, Fareed J, The effect of molecular weight on the bioavailability of heparin. Thrombosis Research 48: 591–596, 1987CrossRefGoogle Scholar
  23. Emmanouel DS, Fang VS, Katz AI. Prolactin metabolism in the rat: role of the kidney in degradation of the hormone. American Journal of Physiology 240: F437–F445. 1981PubMedGoogle Scholar
  24. Emmanouel DS, Goldwasser E, Katz AI. Metabolism of pure human erythropoietin in the rat. American Journal of Physiology 247: F168–FI76. 1984PubMedGoogle Scholar
  25. Emmanouel DS, Jaspan JB, Rubenstein AH, Huen AH-J, Fink E, et al. Glucagon metabolism in the rat Contribution of the kidney to the metabolic clearance rate of the hormone. Journal of Clinical Investigation 62: 6–13, 1978PubMedCrossRefGoogle Scholar
  26. Eschbach JW, Egrie JC, Downing MR, Browne JK, Adamson JW. Correction of the anemia of end-stage renal disease with recombinant human erythropoietin. New England Journal of Medicine 316: 73–78, 1987PubMedCrossRefGoogle Scholar
  27. Eschbach JW, Kelly MR, Haley NR, Abels RI, Adamson JW. Treatment of the anemia of progressive renal failure with recombinant human erythropoietin. New England Journal of Medicine 321: 158–163, 1989PubMedCrossRefGoogle Scholar
  28. Eschbach JW, Mladenovic J, Garcia JF, Wahl PW, Adamson JW. The anemia of chronic renal failure in sheep. Response to erythropoietin-rich plasma in vivo Journal of Clinical Investigation 74: 434–441, 1984Google Scholar
  29. Faulds D, Sorkm EM. Epoetin (Recombinant Human Erythropoietin): A review of us pharmacodynamic and pharmacokinetic properties and therapeutic potential in anaemia and the stimulation of erythropoiesis. Drugs 38: 863–899, 1989PubMedCrossRefGoogle Scholar
  30. Fischer S. Roheim PS Role of liver in the inactivation of erythropoietin. Nature 200: 899–900, 1963PubMedCrossRefGoogle Scholar
  31. Fisher JW. Extrarenal erythropoietin production. Journal of Laboratory and Clinical Medicine 93: 695–699, 1979PubMedGoogle Scholar
  32. Frenken LAM, Coppens PJW, Tiggeler RGWL. Koene RAP In-traperitoneal erythropoietin. Lancet 2: 1495. 1988PubMedCrossRefGoogle Scholar
  33. Fried W. The liver as a source of extrarenal erythropoietin pro-duction. Blood 40: 671–677, 1972PubMedGoogle Scholar
  34. Fu J-S, Lertora JJL, Brookins J, Rice JC, Fisher JW. Pharmacokinetics of erythropoietin in intact and anephric dogs. Journal of Laboratory and Clinical Medicine 111: 669–676, 1988PubMedGoogle Scholar
  35. Fukuda MN, Sasaki H, Lopez L, Fukuda M. Survival of recombinant erythropoietin in the circulation: the role of carbohydrates. Blood 73: 84–89, 1989PubMedGoogle Scholar
  36. Gahl GM, Passlick J, Pustelnik A, Kampf D, Grabensee B, et al. Intraperitoneal versus intravenous recombinant human erythropoietin in stable CAPD patients. 26th Congress of the European Dialysis and Transplant Association — European Renal Association. Gothenburg. Abstract, p. 199, 1989Google Scholar
  37. Galloway JA, Spradlin CT, Nelson RL, Wentworth SM, Davidson JA. el al. Factors influencing ihe absorption, serum insulin concentration, and blood glucose responses after injeclions of regular insulin and various insulin mixtures. Diabetes Care 4: 366–376, 1981PubMedCrossRefGoogle Scholar
  38. Galpin J, Thompkins J, Abels R, Turpen TJ. A study of the safely and efficacy of recombinant human erythropoietin in AIDS patients with anaemia induced by their disease and zidovudine therapy. Vth International Conference on AIDS, Montreal. MBP 328. 1989Google Scholar
  39. Garcia J, Sherwood J, Goldwasser E. Radioimmunoassay of erythropoietin. Blood Cells 5: 405–419, 1979PubMedGoogle Scholar
  40. George WJ, Briggs DW, Rodgers GM, Fisher JW. Metabolism of erythropoietin. In Fisher (Ed.) Kidney Hormones. Vol. II: Erythropoietin, p. 73. Academic Press Inc., London/New York. 1977Google Scholar
  41. Goldwasser E, Kung CK-H. Progress in the purification of erythropoietin. Annals of the New York Academy of Sciences 149: 49–53, 1968PubMedCrossRefGoogle Scholar
  42. Goodnough LT, Rudnick S, Price TH. Increased preoperative collection of autologous blood with recombinant human erythropoietin therapy. New England Journal of Medicine 321: 1163–1168, 1989PubMedCrossRefGoogle Scholar
  43. Granolleras C, Branger B, Beau MC, Deschodt G, Alsabadani B. et al. Experience with daily self-administered subcutaneous erythropoietin. Contributions to Nephrology 76: 143–148, 1989PubMedGoogle Scholar
  44. Hughes RT, Cotes PM, Oliver DO, Pippard MJ, Royston P. et al. Correction of the anaemia of chronic renal failure with erythropoietin: pharmacokinetic studies in patients on haemo-dialysis and CAPD. Contributions to Nephrology 76: 122–130, 1989PubMedGoogle Scholar
  45. Jacobs K, Shoemaker C, Rudcrsdorf R, Neill SD, Kaufman RJ. et al. Isolation and characterization of genomic and cDNA clones of human erythropoietin. Nature 313: 806–810, 1985PubMedCrossRefGoogle Scholar
  46. Jacobson LO, Goldwasser E, Fried W, Plzak LF. The role of the kidney in erythropoiesis. Nature 179: 633–634, 1957PubMedCrossRefGoogle Scholar
  47. Jelkmann W. Temporal pattern of erythropoietin titres in kidney tissue during hypoxic hypoxia. Pflugers Archiv 393: 88–91, 1982PubMedCrossRefGoogle Scholar
  48. Kampf D, Kahl A, Passlick J, Pustelnik A, Eckardt K-U. et al. Single-dose kinetics of recombinant human erythropoietin after intravenous, subcutaneous and intraperitoneal administration. Contributions to Nephrology 76: 106–111, 1989PubMedGoogle Scholar
  49. Katz AI, Rubenstein AH, Metabolism of proinsulin, insulin and C-peptide in the rat. Journal of Clinical Investigation 52: 11 13–1 121. 1973Google Scholar
  50. Kazal LA, Erslev AJ. The measurement of erythropoietin. Annals of Clinical and Laboratory Science 5: 91–97, 1975PubMedGoogle Scholar
  51. Kindlcr J, Eckardt K-U. Ehmer B, Jandeleit K, Kurtz A. et al. Single-dose pharmacokinetics of recombinant human erythropoietin in patients with various degrees of renal failure. Nephrology. Dialysis, Transplantation 4: 345–349, 1989Google Scholar
  52. Koury ST, Bondurant MC, Koury MJ. Localisation of erythropoietin synthesizing cells in murine kidneys by in situ hybridisation. Blood 71: 524–527, 1988PubMedGoogle Scholar
  53. Kromer G, Solf A, Ehmer B, Kaufmann B, Quellhorst E. Single dose pharmacokinetics of recombinant human erythropoietin comparing intravenous, subcutaneous and intraperitoneal administration in 1PD patients. Kidney International 37: 331, 1990Google Scholar
  54. KukraI J, Carney AI, Ebroon E. The role of the liver and surgical stress. Surgical Forum 19: 348–349, 1968Google Scholar
  55. Kurtz A, Eckardt K-U. Tannahill L, Bauer C. Regulation of erythropoietin production. Contributions to Nephrology 66: 1–16, 1988PubMedGoogle Scholar
  56. Lacombe C, DaSilva JL, Bruneval P, Fournier JG, Wendung F, et al. Peritubular cells are the site of erythropoietin synthesis in the murine hypoxic kidney. Journal of Clinical Investigation 81: 620–623, 1988PubMedCrossRefGoogle Scholar
  57. Levine EA, Rosen AL, Gould SA. Recombinant human erythropoietin and autologous blood donation. Surgery 104: 365–369, 1988PubMedGoogle Scholar
  58. Lim VS, DeGowin RL, Zavala D, Kirchner PT, Abels R, et al. Recombinant human erythropoietin treatment in pre-dialysis patients: a double-blind placebo-controlled trial. Annals of Internal Medicine 110: 108–114, 1989PubMedGoogle Scholar
  59. Lin FK, Suggs S, Lin CH, Browne JK, Smalling R, et al. Cloning and expression of the human erythropoietin gene. Proceedings of the National Academy of Sciences of the United Stales of America 82: 7580–7585, 1985CrossRefGoogle Scholar
  60. Macdougall IC, Cavill I, Davies ME, Hutton RD, Coles GA, et al. Subcutaneous recombinant erythropoietin in the treatment of renal anaemia in CAPD patients. Contributions to Nephrology 76: 219–226, 1989aPubMedGoogle Scholar
  61. Macdougall IC, Roberts DE, Coles GA, Williams JD. Intraperitoneal erythropoietin. Lancet 1: 1389, 1989bPubMedCrossRefGoogle Scholar
  62. Macdougall IC, Roberts DE, Neubert P, Dharmasena AD, Coles GA, et al. Pharmacokinetics of intravenous, intraperitoneal, and subcutaneous recombinant erythropoietin in patients on CAPD. Contributions to Nephrology 76: 112–121, 1989cPubMedGoogle Scholar
  63. Macdougall IC, Roberts DE, Neubert P, Dharmasena AD, Coles GA, et al. Pharmacokinetics of recombinant human erythropoietin in patients on continuous ambulatory peritoneal dialysis. Lancet 2: 425–427, 1989dCrossRefGoogle Scholar
  64. Maxwell AP, Douglas JF, Afrasiabi M, Lappin TRJ, Bridges JM. Erythropoietin pharmacokinetics and red cell metabolism in haemodialysis patients. Nephrology, Dialysis. Transplantation 4: 476, 1989aGoogle Scholar
  65. Maxwell AP, Lappin TRJ, Bridges JM, Johnston CF, McGeown MG. Renal tubular cell production of erythropoietin co-localised by immunohistochemistry and in situ hybridisation. Nephrology. Dialysis, Transplantation 4: 420, 1989bGoogle Scholar
  66. Means RT, Olsen NJ, Krantz SB, Dessypris EN, Graber SE, et al. Treatment of the anemia of rheumatoid arthritis with recombinant human erythropoietin: clinical and in vitro studies. Arthritis and Rheumatism 32: 638–642, 1989PubMedCrossRefGoogle Scholar
  67. Milledge JS, Cotes PM. Serum erythropoietin in humans at high altitude and its relation to plasma renin. Journal of Applied Physiology 59: 360–364, 1985PubMedGoogle Scholar
  68. Miyake T, Kung CKH, Goldwasser E. Purification of human erythropoietin. Journal of Biological Chemistry 252: 5558–5564. 1977PubMedGoogle Scholar
  69. Mladenovic J, Eschbach JW, Koup JR, Garcia JF, Adamson JW. Erythropoietin kinetics in normal and uremic sheep. Journal of Laboratory and Clinical Medicine 105: 659–663, 1985PubMedGoogle Scholar
  70. Naets JP, Wittek M. A role of the kidney in the catabolism of erythropoietin in the rat. Journal of Laboratory and Clinical Medicine 84: 99–106, 1974PubMedGoogle Scholar
  71. Neumayer H-H, Brockmoller J, Fritschka E, Roots I, Scigalla P. et al. Pharmacokinetics of recombinant human erythropoietin after SC administration and in long-term IV treatment in patients on maintenance hemodialysis. Contributions to Nephrology 76: 131–142, 1989PubMedGoogle Scholar
  72. Nielsen OJ, Egfjord M, Hirth P. Erythropoietin metabolism in the isolated perfused rat liver. Contributions to Nephrology 76: 90–97, 1989PubMedGoogle Scholar
  73. Paulsen EP, Courtney JW, Duckworth WC. Insulin resistance caused by massive degradation of subcutaneous insulin. Diabetes 28: 640–645, 1979PubMedCrossRefGoogle Scholar
  74. Recny MA, Scoble HA, Kim Y. Structural characterisation of natural human urinary and recombinant DNA-derivcd erythropoietin (identification of des-Arginine 166 erythropoietin). Journal of Biological Chemistry 262: 17156–17163, 1987PubMedGoogle Scholar
  75. Reissmann KR, Diederich KA, Kenjiro I, Schmaus JW. Influence of disappearance rate and distribution space on plasma concentration of erythropoietin in normal rats. Journal of Laboratory and Clinical Medicine 65: 967–975, 1965PubMedGoogle Scholar
  76. Rhondeau SM, Christensen RD, Ross MP, Rothstein G, Simmons MA. Responsiveness to recombinant human erythropoietin of marrow erythroid progenitors from infants with the “anemia of prematurity”. Journal of Pediatrics 112: 935–940, 1988PubMedCrossRefGoogle Scholar
  77. Roh BL, Paulo G, Fisher JW. Metabolism of erythropoietin by isolated perfused livers of dogs treated with SKF 525-A. American Journal of Physiology 223: 1345–1348, 1972aPubMedGoogle Scholar
  78. Roh BL, Paulo LG, Thompson J, Fisher JW. Plasma disappearance of 125I-labelled erythropoietin in anesthetised rabbits. Proceedings of the Society for Experimental Biology and Medicine 141: 268–270, 1972bPubMedGoogle Scholar
  79. Rosse WF, Waldmann TA. The metabolism of erythropoietin in patients with anemia due to deficient erythropoiesis. Journal of Clinical Investigation 43: 1348–1354, 1964PubMedCrossRefGoogle Scholar
  80. Salmonson T, Danielson BG, Wikstrom B. Pharmacokinetics and pharmacodynamics of recombinant erythropoietin after SC and IV administration. 26th Congress of the European Dialysis and Transplant Association — European Renal Association. Gothenburg. Abstract, p. 210, 1989Google Scholar
  81. Sasaki H, Bothner B, Dell A, Fukuda M. Carbohydrate structure of erythropoietin expressed in Chinese hamster ovary cells by a human erythropoietin cDNA. Journal of Biological Chemistry 262; 12059–12076. 1987PubMedGoogle Scholar
  82. Sawyer ST, Krantz SB, Goldwasser E. Binding and receptor-mediated endocytosis of erythropoietin in Friend virus-infected erythroid cells. Journal of Biological Chemistry 262: 5554–5562, 1987PubMedGoogle Scholar
  83. Scigalla P, Hoelk G, Pahlke W. Pharmacokinetics of recombinant erythropoietin in normal and uraemic rats. Nephrology, Dialysis. Transplantation 2: 389, 1987Google Scholar
  84. Shannon KM, Naylor GS, Torkildson JC, Circulating erythroid progenitors in the anemia of prematurity. New England Journal of Medicine 317: 728–733, 1987PubMedCrossRefGoogle Scholar
  85. Sherwood JB, Carmichael LD, Goldwasser E. The heterogeneity of circulating human serum erythropoietin. Endocrinology 122: 1472–1477, 1988PubMedCrossRefGoogle Scholar
  86. Sinai-Trieman L, Salusky IB, Fine RN. Use of subcutaneous recombinant human erythropoietin in children undergoing continuous cycling peritoneal dialysis. Journal of Pediatrics 114: 550–554, 1989PubMedCrossRefGoogle Scholar
  87. Spivak JL, Hogans BB. The in vivo metabolism of recombinant human erythropoietin in the rat. Blood 73: 90–99, 1989PubMedGoogle Scholar
  88. Steinhauer HB, Lubrich-Birkner I, Dreyling KW, Horl WH, Schollmeyer P. Increased ultrafiltration after erythropoietin-induced correction of renal anemia in patients on continuous ambulatory peritoneal dialysis. Nephron 53: 87–88, 1989CrossRefGoogle Scholar
  89. Stevens JM, Strong CA, Oliver DO, Winearls CG, Cotes PM. Subcutaneous erythropoietin and peritoneal dialysis. Lancet 1: 1388–1389, 1989PubMedCrossRefGoogle Scholar
  90. Walker RE, Parker RI, Kovacs JA. Anemia and erythropoiesis in patients with the acquired immunodeficiency syndrome and Kaposi’s sarcoma treated with zidovudine. Annals of Internal Medicine 108: 372–376, 1988PubMedGoogle Scholar
  91. Weintraub AH, Gordon AS, Becker EL, Camiscoli JF, Contrera JF. Plasma and renal clearance of exogenous erythropoietin in the dog. American Journal of Physiology 207: 523–529, 1964PubMedGoogle Scholar
  92. Wikstrom B, Salmonson T, Grahnen A, Danielson BG. Phar-macokineiics of recombinant human erythropoietin in haemo dialysis patients. Nephrology, Dialysis, Transplantation 3: 503 1988Google Scholar
  93. Wilton P, Widlund L, Guilbaud. Bioequivalence of genotropit and somatonorm. Acta Paediatrica Scandinavica 337 (Suppl.) 118–121, 1987PubMedCrossRefGoogle Scholar
  94. Winearls CG, Oliver DO, Pippard MJ, Reid C, Downing MR, et al. Effect of human erythropoietin derived from recombinan DNA on the anaemia of patients maintained by chronii haemodialysis. Lancet 2: 1175–1178, 1986PubMedCrossRefGoogle Scholar

Copyright information

© Adis International Limited 1991

Authors and Affiliations

  • Iain C. Macdougall
    • 1
    • 2
  • David E. Roberts
    • 1
    • 2
  • Gerald A. Coles
    • 1
    • 2
  • John D. Williams
    • 1
    • 2
  1. 1.Institute of NephrologyUniversity of Wales College of Medicine, Royal InfirmaryCardiffUK
  2. 2.Department of PharmacyUniversity Hospital of WalesCardiff, WalesUK

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