Abstract
After oral or parenteral administration of chemotherapeutic agents, these drugs are transported to the tissues by the blood in different fractions: plasma water, plasma proteins or cells. Erythrocytes may play an important role in the storage, transport and metabolism of chemotherapeutic agents.
Anthracyclines, ifosfamide and its metabolites, and topoisomerase I and I/II inhibitors are incorporated in red blood cells. They may be transported to the tumour tissue and mobilised from the erythrocyte by different active or passive transport mechanisms. Erythrocytes may also be used as carriers for drugs such as asparaginase. This leads to a decreased toxicity profile.
Finally, it has been shown that red blood cells are important in the transport and metabolism of mercaptopurine. The erythrocyte concentration of mercaptopurine has a prognostic value in the treatment of childhood acute lymphoblastic leukemia.
In this review, the role of red blood cells for various anticancer drugs is further discussed.
Similar content being viewed by others
References
Hsia CCW. Mechanisms of disease: respiratory function of hemoglobin. N Engl J Med 1998; 4: 239–47
Highley MS, De Bruijn EA. Erythrocytes and the transport of drugs and endogenous compounds. Pharm Res 1996; 13: 186–95
Kirk K. Membrane transport in the malaria-infected erythrocyte. Physiol Rev 2001; 81: 495–537
Sharma R, Singhal S, Cheng J, et al. RLIP76 is the major ATP-dependent transporter of glutathione-conjugates and doxorubicin in human erythrocytes. Arch Biochem Biophys 2001; 391: 171–9
Chen Z, Lee K, Walther S, et al. Analysis of methotrexate and folate transport by multidrug resistance protein 4 (ABCC4): MRP4 is a component of the methotrexate efflux system. Cancer Res 2002; 62: 3144–50
Krug G, Zeng H, Rea P, et al. MRP subfamily transporters and resistance to anticancer agents. J Bioenerg Biomembr 2001; 33: 493–501
Krants A. Red cell-mediated therapy: opportunities and challenges. Blood Cells Mol Dis 1997; 23: 58–68
Griffiths M, Beaumont N, Yao S, et al. Cloning of a human nucleoside transported implicated in the cellular uptake of adenosine and chemotherapeutic drugs. Nat Med 1997; 3: 89–93
Mawatari J, Unei K, Nischimuara S, et al. Comparative pharmacokinetics of oral 6-mercaptopurine and intravenous 6-mercaptomurine riboside in children. Pediatr Int 2001; 43: 673–7
Keuzenkamp-Jansen CW, De Abreu RA, Bokkerink JPM, et al. Determination of extracellular and intracellular thiopurines and methylthiopurines by high-performance liquid chromatography. J Chromatogr B Biomed Appl 1995; 672: 53–61
Rabel SR, Stobaugh JF, Trueworthy R. Determination of intracellular levels of 6-mercaptopurine metabolites in erythrocytes utilizing capillary electrophoresis with laser-induced fluorescence detection. Anal Biochem 1995; 224: 315–22
Rostami-Hodjegan A, Lennard L, Lilleyman JS. The accumulation of mercaptopurine metabolites in age fractionated red blood cells. Br J Clin Pharmacol 1995; 40: 217–22
McLeod H, Relling M, Evans W. Genetic polymorphism of thiopurine and its clinical relevance for childhood acute lymphoblastic leukaemia. Leukemia 2000; 14: 576–2
Wijnholds J, Mol C, van Deemter L, et al. Multidrug-resistance protein 5 is a multispecific organic anion transporter able to transport nucleotide analogs. Proc Natl Acad Sci U S A 2000; 97: 7476–81
Bostrom B, Erdmann G. Cellular pharmacology of 6-mercaptopurine in acute lymphoblastic leukemia. Am J Pediatr Hematol Oncol 1993; 15: 80–6
Lennard L, Davies H, Lilleyman JS. Is 6-thioguanine more appropriate than 6-mercaptopurine for children with acute lymphoblastic leukaemia?. Br J Cancer 1993; 68: 186–90
Lowe E, Kitchen N, Erdmann G, et al. Plasma pharmacokinetics and cerebrospinal fluid penetration of thioguanine in children with acute lymphoblastic leukaemia: a collaborative Pediatric Oncology Branch, NCI, and Children’s Cancer Group study. Cancer Chemother Pharmacol 2001; 47: 199–205
Erb N, Harms D, Janka-Schaub G. Pharmacokinetics and metabolism of thiopurines in children with acute lymphoblastic leukemia receiving 6-thioguanine versus 6-mercaptopurine. Cancer Chemother Pharmacol 1998; 42: 266–72
Lena N, Imbert AM, Brunet P, et al. Kinetics of methotrexate and its metabolites in red blood cells. Cancer Drug Deliv 1987; 4: 119–27
Flynn G, McHale L, McHale AP. Methotrexate-loaded, photosensitized erythrocytes: a photo-activatable carrier/delivery system for use in cancer therapy. Cancer Lett 1994; 82: 225–9
Schroder H, Clausen N, Ostergard E, et al. Folic acid supplements in vitamin tablets: a determinant of hematological drug tolerance in maintenance therapy of childhood acute lymphoblastic leukemia. Pediatr Hematol Oncol 1986; 3: 241–7
Graham ML, Shuster JJ, Kamen BA, et al. Red blood cell methotrexate and folate levels in children with acute lymphoblastic leukemia undergoing therapy: a Pediatrie Oncology Group pilot study. Cancer Chemother Pharmacol 1992; 31: 217–22
Schmiegelow K, Schroder H, Gustafsson G, et al. Risk of relapse in childhood acute lymphoblastic leukemia is related to RBC methotrexate and mercaptopurine metabolites during maintenance chemotherapy. Nordic Society of Pediatrie Hematology and Oncology. J Clin Oncol 1995; 13: 345–51
Balis F, Holcenberg J, Poplack D, et al. Pharmacokinetics and pharmacodynamics of oral methotrexate and mercaptopurine in children with lower risk acute lymphoblastic leukaemia: a joint Children’s Cancer Group and Pediatrie Oncology Branch Study. Blood 1998; 92: 3569–77
Wattanatorn W, McLeod HL, Cassidy J, et al. High-performance liquid Chromatographie assay of 5-fluorouracil in human erythrocytes, plasma and whole blood. J Chromatogr B Biomed Appl 1997; 692: 233–7
Czejka M, Schüller J, Fogl U. Pharmakokinetik von 5-Fluorouracil nach i.v.-gabe unter ber: ucksichtigung der erythrozyten. Arch Pharm 1992; 325: 73–5
Baerlocher GM, Beer JH, Owen GR, et al. The anti-neoplastic drug 5-fluorouracil produces echinocytosis and affects blood rheology. Br J Haematol 1997; 99: 426–33
Kravtzoff R, Colombat P, Desbois I, et al. Tolerance evaluation of L-asparaginase loaded in red blood cells. Eur J Clin Pharmacol 1996; 51: 221–5
Colombo T, Broggini M, Garattini S, et al. Differential adriamycin distribution to blood components. Eur J Drug Metab Pharmacokinet 1981; 6: 115–22
De Flora A, Benatti U, Guida L, et al. Encapsulation of adriamycin in human erythrocytes. Proc Natl Acad Sci U S A 1986; 83: 7029–33
Singal PK, Iliskovic N. Doxorubicin-induced cardiomyopathy. N Eng J Med 1998; 339: 900–5
Waterhouse D, Tardi P, Mayer L, et al. A comparison of liposomal formulations of doxorubicin with drug administered in free form: changing toxicity profiles. Drug Saf 2001; 24(12): 903–20
Czejka MJ, Schüller J, Weiss C, et al. Disposition of epirubicin and its aglycone in serum and red blood cells after high-dose i.v. bolus. Int J Exp Clin Chemother 1992; 5: 193–8
Pernkopf I, Tesch G, Dempe K, et al. In vitro-untersuchungen zur binding von epirubicin an humane plasmaproteine und erythrozyten: interaktion mit dem zytoprotektivum amifostin. Pharmazie 1996; 51: 897–901
Bandak S, Czejka M, Schüller J, et al. Pharmacokinetic drug interaction between epirubicin and interferon-alfa-2b in serum and red blood cells. Arzneimittelforschung Drug Res 1995; 45: 212–5
Lachatre F, Marquet P, Ragot S, et al. Simultaneous determination of four anthracyclines and three metabolites in human serum by liquid chemotheragraphy-electrospray mass spectrometry. J Chromatogr B Biomed Sci Appl 2000; 738: 281–91
Ataullakhanov F, Batasheva T, Vitvitskii V. Effect of temperature, daunorubicin concentration and suspension hematocrit on daunorubicin binding by human erythrocytes. Antibiot Khimioter 1994; 39: 26–9
Robert J, Rigal-Huguet F, Hurteloup P. Comparative pharmacokinetic study of idarubicin and daunorubicin in leukemia patients. Hematol Oncol 1992; 10: 111–6
Vermorken JB, van der Vijgh WJF, Klein I, et al. Pharmacokinetics of free and total platinum species after short-term infusion of cisplatin. Cancer Treat Rep 1984; 68: 505–13
Van Der Vijgh WJF. Clinical pharmacokinetics of carboplatin. Clin Pharmacokinet 1991; 21: 242–61
Long DF, Patton TF, Repta AJ. Platinum levels in human erythrocytes following intravenous administration of cisplatin: importance of erythrocytes as a distribution site for platinum species. Biopharm Drugs Dispos 1981; 2: 137–46
Elferink F, Van der Vijgh WJF, Klein I, et al. Pharmacokinetics of carboplatin after i.v. administration. Cancer Treat Rep 1987; 71: 1231–7
Allain P, Heudi O, Cailleux A, et al. Early biotransformations of oxaliplatin after its intravenous administration to cancer patients. Drug Metab Dispos 2000; 28: 1379–84
Grumblat A, Peytavin G, Vayre P, et al. Pharmacokinetics of oxaliplatin compared after intraperitoneal and intravenous administration. Bull Cancer 1989; 76: 887–8
Gamelin E, Le Bouil A, Boisdron-Celle M, et al. Cumulative pharmacokinetic study of oxaliplatin, administered every three weeks, combined with 5-fluorouracil in colorectal cancer patients. Clin Cancer Res 1997; 3: 891–9
Massari C, Brienza S, Rotarski M, et al. Pharmacokinetics of oxaliplatin in patients with normal versus impaired renal function. Cancer Chemother Pharmacol 2000; 45: 157–64
Pendyala L, Creaven PJ. In vitro cytotoxicity, protein binding, red blood cell partitioning, and biotransformation of oxaliplatin. Cancer Res 1993; 53: 5970–6
Dechant KL, Brogden RN, Pilkington T, et al. Ifosfamide/mesna: a review of its antineoplastic activity, pharmacokinetic properties and therapeutic efficacy in cancer. Drugs 1991; 42: 428–67
Momerency G, Van Cauwenberghe K, Highley MS, et al. Partitioning of ifosfamide and its metabolites between red blood cells and plasma. J Pharm Sci 1996; 85: 262–5
Highley MS, Schrijvers D, Van Oosterom AT, et al. Activated oxazaphosphorines are transported predominantly by erythrocytes. Ann Oncol 1997; 8: 1139–44
Kerbusch T, Herben V, Jeuken M, et al. Distribution of ifosfamide and metabolites between plasma and erythrocytes. Biopharm Drug Dispos 2001; 22: 99–108
Reuther H, Kohl MP, Wildenauer D. The interaction of mesna and dimesna with the sulfate exchange in red blood cells. Arzneimittel Forschung 1986; 36: 763–5
Souid A, Fahey R, Aktas M, et al. Blood thiols following amifostine and mesna infusions, a Pediatric Oncology Group study. Drug Metab Dispos 2001; 29: 1460–6
Kumar GN, Walle UK, Bhalla KN, et al. Binding of taxol to human plasma, albumin and alpha 1-acid glycoprotein. Res Commun Chem Pathol Pharmacol 1993; 80: 337–44
Mi Z, Burke TG. Differential interactions of camptothecin lactone and carboxylate forms with human blood components. Biochemistry 1994; 33: 10325–36
Loos W, van Zomeren D, Gelderblom H, et al. Determination of topotecan in human whole blood and unwashed erythrocytes by high-performance liquid chromatography. J Chromatogr B 2002; 766: 99–105
Anbigerges D, Armand P, Chabot G, et al. Phase I and pharmacologic study of intoplicine (RP 60475; NSC 645008), a novel topoisomerase I and II inhibitor, in cancer patients. Anticancer Drugs 1996; 7: 166–74
Acknowledgements
No sources of funding were used to assist in the preparation of this article. The author has no conflicts of interest that are directly relevant to the content of this article.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Schrijvers, D. Role of Red Blood Cells in Pharmacokinetics of Chemotherapeutic Agents. Clin Pharmacokinet 42, 779–791 (2003). https://doi.org/10.2165/00003088-200342090-00001
Published:
Issue Date:
DOI: https://doi.org/10.2165/00003088-200342090-00001