Clinical Pharmacokinetics

, Volume 45, Issue 9, pp 871–903 | Cite as

Pharmacokinetic Considerations in the Treatment of CNS Tumours

  • Susannah Motl
  • Yanli Zhuang
  • Christopher M. Waters
  • Clinton F. Stewart
Review Article


Despite aggressive therapy, the majority of primary and metastatic brain tumour patients have a poor prognosis with brief survival periods. This is because of the different pharmacokinetic parameters of systemically administered chemotherapeutic agents between the brain and the rest of the body. Specifically, before systemically administered drugs can distribute into the CNS, they must cross two membrane barriers, the blood-brain barrier (BBB) and blood-cerebrospinal fluid (CSF) barrier (BCB). To some extent, these structures function to exclude xenobiotics, such as anticancer drugs, from the brain. An understanding of these unique barriers is essential to predict when and how systemically administered drugs will be transported to the brain. Specifically, factors such as physiological variables (e.g. blood flow), physicochemical properties of the drug (e.g. molecular weight), as well as influx and efflux transporter expression at the BBB and BCB (e.g. adenosine triphosphate-binding cassette transporters) determine what compounds reach the CNS. A large body of preclinical and clinical research exists regarding brain penetration of anticancer agents. In most cases, a surrogate endpoint (i.e. CSF to plasma area under the concentration-time curve [AUC] ratio) is used to describe how effectively agents can be transported into the CNS. Some agents, such as the topoisomerase I inhibitor, topotecan, have high CSF to plasma AUC ratios, making them valid therapeutic options for primary and metastatic brain tumours. In contrast, other agents like the oral tyrosine kinase inhibitor, imatinib, have a low CSF to plasma AUC ratio. Knowledge of these data can have important clinical implications. For example, it is now known that chronic myelogenous leukaemia patients treated with imatinib might need additional CNS prophylaxis. Since most anticancer agents have limited brain penetration, new pharmacological approaches are needed to enhance delivery into the brain. BBB disruption, regional administration of chemotherapy and transporter modulation are all currently being evaluated in an effort to improve therapeutic outcomes. Additionally, since many chemotherapeutic agents are metabolised by the cytochrome P450 3A enzyme system, minimising drug interactions by avoiding concomitant drug therapies that are also metabolised through this system may potentially enhance outcomes. Specifically, the use of non-enzyme-inducing antiepileptic drugs and curtailing nonessential corticosteroid use may have an impact.


  1. 1.
    American Cancer Society. Cancer facts and figures 2006 [online]. Available from URL: [Accessed 2006 Jul 28]
  2. 2.
    Parkin DM, Bray F, Ferlay J, et al. Estimating the world cancer burden: Globocan 2000. Int J Cancer 2001; 94: 153–6PubMedGoogle Scholar
  3. 3.
    About adult brain tumors: City of Hope web site [online]. Available from URL: [Accessed 2006 Mar 8]
  4. 4.
    Central brain tumor registry of the US (CBTRUS) data [online]. Available from URL: [Accessed 2005 Mar 8]
  5. 5.
    Baldwin RT, Preston-Martin S. Epidemiology of brain tumors in childhood: a review. Toxicol Appl Pharmacol 2004; 199: 118–31PubMedGoogle Scholar
  6. 6.
    Deangelis LM. Brain tumors. N Engl J Med 2001; 344: 114–23PubMedGoogle Scholar
  7. 7.
    Finlay JL, Zacharoulis S. The treatment of high grade gliomas and diffuse intrinsic pontine tumors of childhood and adolescence: a historical- and futuristic — perspective. J Neurooncol 2005; 75: 253–66PubMedGoogle Scholar
  8. 8.
    Davson H, Segal MB. Physiology of the CSF and blood-brain barriers. Boca Raton (FL): CRC Press Inc., 1996Google Scholar
  9. 9.
    Zheng W, Aschner M, Ghersi-Egea JF. Brain barrier systems: a new frontier in metal neurotoxicological research. Toxicol Appl Pharmacol 2003; 192: 1–11PubMedGoogle Scholar
  10. 10.
    Oldendorf WH, Cornford ME, Brown WJ. The large apparent work capability of the blood-brain barrier: a study of the mitochondrial content of capillary endothelial cells in brain and other tissues of the rat. Ann Neurol 1977; 1: 409–17PubMedGoogle Scholar
  11. 11.
    Pardridge WM, Oldendorf WH, Cancilla P, et al. Blood-brain barrier: interface between internal medicine and the brain. Ann Intern Med 1986; 105: 82–95PubMedGoogle Scholar
  12. 12.
    Abbott NJ. Dynamics of CNS barriers: evolution, differentiation, and modulation. Cell Mol Neurobiol 2005; 25: 5–23PubMedGoogle Scholar
  13. 13.
    Loscher W, Potschka H. Drug resistance in brain diseases and the role of drug efflux transporters. Nat Rev Neurosci 2005; 6(8): 591–602PubMedGoogle Scholar
  14. 14.
    Vorbrodt AW, Dobrogowska DH. Molecular anatomy of intercellular junctions in brain endothelial and epithelial barriers: electron microscopist’s view. Brain Res Brain Res Rev 2003; 42: 221–42PubMedGoogle Scholar
  15. 15.
    Kusuhara H, Sugiyama Y. Active efflux across the blood-brain barrier: role of the solute carrier family. NeuroRx 2005; 2: 73–85PubMedGoogle Scholar
  16. 16.
    Ito K, Suzuki H, Horie T, et al. Apical/Basolateral surface expression of drug transporters and its role in vectorial drug transport. Pharm Res 2005; 22: 1559–77PubMedGoogle Scholar
  17. 17.
    Loscher W, Potschka H. Blood-brain barrier active efflux transporters: ATP-binding cassette gene family 1. NeuroRx 2005; 2: 86–98PubMedGoogle Scholar
  18. 18.
    Schinkel AH, Smit JJ, van Tellingen O, et al. Disruption of the mouse mdr1a P-glycoprotein gene leads to a deficiency in the blood-brain barrier and to increased sensitivity to drugs. Cell 1994; 77: 491–502PubMedGoogle Scholar
  19. 19.
    Loscher W, Potschka H. Role of drug efflux transporters in the brain for drug disposition and treatment of brain diseases. Prog Neurobiol 2005; 76: 22–76PubMedGoogle Scholar
  20. 20.
    Pardridge WM. The blood-brain barrier: bottleneck in brain drug development. NeuroRx 2005; 2: 3–14PubMedGoogle Scholar
  21. 21.
    Johanson CE, Duncan JA, Stopa EG, et al. Enhanced prospects for drug delivery and brain targeting by the choroid plexus-CSF route. Pharm Res 2005; 22: 1011–37PubMedGoogle Scholar
  22. 22.
    Redzic ZB, Segal MB. The structure of the choroid plexus and the physiology of the choroid plexus epithelium. Adv Drug Deliv Rev 2004; 56: 1695–716PubMedGoogle Scholar
  23. 23.
    Strazielle N, Ghersi-Egea JF. Choroid plexus in the central nervous system: biology and physiopathology. J Neuropathol Exp Neurol 2000; 59: 561–74PubMedGoogle Scholar
  24. 24.
    Keep RF, Jones HC. A morphometric study on the development of the lateral ventricle choroid plexus, choroid plexus capillaries and ventricular ependyma in the rat. Brain Res Dev Brain Res 1990; 56: 47–53PubMedGoogle Scholar
  25. 25.
    Miyan J, Nibayouni M, Zendah M. Development of the brain: a vital role for cerebrospinal fluid. Canadian J Physiol and Pharmacol 2003; 81: 317–28Google Scholar
  26. 26.
    De Lange EC, Danhof M. Considerations in the use of cerebrospinal fluid pharmacokinetics to predict brain target concentrations in the clinical setting: implications of the barriers between blood and brain. Clin Pharmacokinet 2002; 41: 691–703PubMedGoogle Scholar
  27. 27.
    Szmydynger-Chodobska J, Chodobski A, Johanson CE. Postnatal developmental changes in blood flow to choroid plexuses and cerebral cortex of the rat. Am J Physiol 1994; 266: R1488–92PubMedGoogle Scholar
  28. 28.
    Ghersi-Egea JF, Minn A, Siest G. A new aspect of the protective functions of the blood-brain barrier: activities of four drug-metabolizing enzymes in isolated rat brain microvessels. Life Sci 1988; 42: 2515–23PubMedGoogle Scholar
  29. 29.
    Ghersi-Egea JF, Strazielle N. Brain drag delivery, drag metabolism, and multidrug resistance at the choroid plexus. Microsc Res Tech 2001; 52: 83–8PubMedGoogle Scholar
  30. 30.
    Vajkoczy P, Menger MD. Vascular microenvironment in gliomas. J Neurooncol 2000; 50: 99–108PubMedGoogle Scholar
  31. 31.
    Van VM, Kal HB, Taphoorn MJ, et al. Changes in blood-brain barrier permeability induced by radiotherapy: implications for timing of chemotherapy? Oncol Rep 2002; 9: 683–8Google Scholar
  32. 32.
    Kemper EM, Boogerd W, Thuis I, et al. Modulation of the blood-brain barrier in oncology: therapeutic opportunities for the treatment of brain tumours? Cancer Treat Rev 2004; 30: 415–23PubMedGoogle Scholar
  33. 33.
    Dukic SF, Kaltenbach ML, Heurtaux T, et al. Influence of C6 and CNS1 brain tumors on methotrexate pharmacokinetics in plasma and brain tissue. J Neurooncol 2004; 67: 131–8PubMedGoogle Scholar
  34. 34.
    Devineni D, Klein-Szanto A, Gallo JM. In vivo microdialysis to characterize drag transport in brain tumors: analysis of methotrexate uptake in rat glioma-2 (RG-2)-bearing rats. Cancer Chemother Pharmacol 1996; 38: 499–507PubMedGoogle Scholar
  35. 35.
    Pardridge WM. Drag delivery to the brain. J Cereb Blood Flow Metab 1997; 17: 713–31PubMedGoogle Scholar
  36. 36.
    Fischer H, Gottschlich R, Seelig A. Blood-brain barrier permeation: molecular parameters governing passive diffusion. J Membr Biol 1998; 165: 201–11PubMedGoogle Scholar
  37. 37.
    Lipinski CA. Drag-like properties and the causes of poor solubility and poor permeability. J Pharmacol Toxicol Methods 2000; 44: 235–49PubMedGoogle Scholar
  38. 38.
    Martin I. Prediction of blood-brain barrier penetration: are we missing the point? Drag Discov Today 2004; 9: 161–2Google Scholar
  39. 39.
    Kusuhara H, Sugiyama Y. Efflux transport systems for organic anions and cations at the blood-CSF barrier. Adv Drag Deliv Rev 2004; 56: 1741–63Google Scholar
  40. 40.
    Rao VV, Dahlheimer JL, Bardgett ME, et al. Choroid plexus epithelial expression of MDR1 P glycoprotein and multidrug resistance-associated protein contribute to the blood-cerebros-pinal-fluid drug-permeability barrier. Proc Natl Acad Sci U S A 1999; 96: 3900–5PubMedGoogle Scholar
  41. 41.
    Andersson U, Malmer B, Bergenheim AT, et al. Heterogeneity in the expression of markers for drag resistance in brain tumors. Clin Neuropathol 2004; 23: 21–7PubMedGoogle Scholar
  42. 42.
    Sawada T, Kato Y, Sakayori N, et al. Expression of the multidrug-resistance P-glycoprotein (Pgp, MDR-1) by endothelial cells of the neovasculature in central nervous system tumors. Brain Tumor Pathol 1999; 16: 23–7PubMedGoogle Scholar
  43. 43.
    Toth K, Vaughan MM, Peress NS, et al. MDR1 P-glycoprotein is expressed by endothelial cells of newly formed capillaries in human gliomas but is not expressed in the neovasculature of other primary tumors. Am J Pathol 1996; 149: 853–8PubMedGoogle Scholar
  44. 44.
    Gottesman MM, Fojo T, Bates SE. Multidrug resistance in cancer: role of ATP-dependent transporters. Nat Rev Cancer 2002; 2: 48–58PubMedGoogle Scholar
  45. 45.
    Egorin MJ, Kaplan RS, Salcman M, et al. Cyclophosphamide plasma and cerebrospinal fluid kinetics with and without dimethyl sulfoxide. Clin Pharmacol Ther 1982; 32: 122–8PubMedGoogle Scholar
  46. 46.
    Yule SM, Price L, Pearson AD, et al. Cyclophosphamide and ifosfamide metabolites in the cerebrospinal fluid of children. Clin Cancer Res 1997; 3: 1985–92PubMedGoogle Scholar
  47. 47.
    Kaijser GP, De KJ, Bult A, et al. Pharmacokinetics of ifosfamide and some metabolites in children. Anticancer Res 1998; 18: 1941–9PubMedGoogle Scholar
  48. 48.
    Ninane J, Baurain R, De KJ, et al. Alkylating activity in serum, urine, and CSF following high-dose ifosfamide in children. Cancer Chemother Pharmacol 1989; 24 Suppl. 1: S2–6PubMedGoogle Scholar
  49. 49.
    Freeman AI, Wang JJ, Sinks LF. High-dose methotrexate in acute lymphocytic leukemia. Cancer Treat Rep 1977; 61: 727–31PubMedGoogle Scholar
  50. 50.
    Gilchrist NL, Caldwell J, Watson ID, et al. Comparison of serum and cerebrospinal fluid levels of methotrexate in man during high-dose chemotherapy for aggressive non-Hodgkin’s lymphoma. Cancer Chemother Pharmacol 1985; 15: 290–4PubMedGoogle Scholar
  51. 51.
    Evans WE, Hutson PR, Stewart CF, et al. Methotrexate cerebrospinal fluid and serum concentrations after intermediatedose methotrexate infusion. Clin Pharmacol Ther 1983; 33: 301–7PubMedGoogle Scholar
  52. 52.
    Morse M, Savitch J, Balis F, et al. Altered central nervous system pharmacology of methotrexate in childhood leukemia: another sign of meningeal relapse. J Clin Oncol 1985; 3: 19–24PubMedGoogle Scholar
  53. 53.
    Reid JM, Pendergrass TW, Krailo MD, et al. Plasma pharmacokinetics and cerebrospinal fluid concentrations of idarubicin and idarubicinol in pediatric leukemia patients: a Childrens Cancer Study Group report. Cancer Res 1990; 50: 6525–8PubMedGoogle Scholar
  54. 54.
    Dreyer ZE, Kadota RP, Stewart CF, et al. Phase 2 study of idarubicin in pediatric brain tumors: Pediatric Oncology Group study POG 9237. Neuro-oncol 2003; 5: 261–7PubMedGoogle Scholar
  55. 55.
    von Holst H, Knochenhauer E, Blomgren H, et al. Uptake of adriamycin in tumour and surrounding brain tissue in patients with malignant gliomas. Acta Neurochir (Wien) 1990; 104: 13–6Google Scholar
  56. 56.
    Baker SD, Heideman RL, Crom WR, et al. Cerebrospinal fluid pharmacokinetics and penetration of continuous infusion topotecan in children with central nervous system tumors. Cancer Chemother Pharmacol 1996; 37: 195–202PubMedGoogle Scholar
  57. 57.
    Stewart CF, Iacono LC, Chintagumpala M, et al. Results of a phase II upfront window of pharmacokinetically guided topotecan in high-risk medulloblastoma and supratentorial primitive neuroectodermal tumor. J Clin Oncol 2004; 22: 3357–65PubMedGoogle Scholar
  58. 58.
    Ostermann S, Csajka C, Buclin T, et al. Plasma and cerebrospinal fluid population pharmacokinetics of temozolomide in malignant glioma patients. Clin Cancer Res 2004; 10: 3728–36PubMedGoogle Scholar
  59. 59.
    Jackson Jr DV, Sethi VS, Spurr CL, et al. Pharmacokinetics of vincristine in the cerebrospinal fluid of humans. Cancer Res 1981; 41: 1466–8PubMedGoogle Scholar
  60. 60.
    Kellie SJ, Barbaric D, Koopmans P, et al. Cerebrospinal fluid concentrations of vincristine after bolus intravenous dosing: a surrogate marker of brain penetration. Cancer 2002; 94: 1815–20PubMedGoogle Scholar
  61. 61.
    Pfeifer H, Wassmann B, Hofmann WK, et al. Risk and prognosis of central nervous system leukemia in patients with Philadelphia chromosome-positive acute leukemias treated with imatinib mesylate. Clin Cancer Res 2003; 9: 4674–81PubMedGoogle Scholar
  62. 62.
    Leis JF, Stepan DE, Curtin PT, et al. Central nervous system failure in patients with chronic myelogenous leukemia lymphoid blast crisis and Philadelphia chromosome positive acute lymphoblastic leukemia treated with imatinib (STI-571). Leuk Lymphoma 2004; 45: 695–8PubMedGoogle Scholar
  63. 63.
    Arndt CA, Balis FM, McCully CL, et al. Cerebrospinal fluid penetration of active metabolites of cyclophosphamide and ifosfamide in rhesus monkeys. Cancer Res 1988; 48: 2113–5PubMedGoogle Scholar
  64. 64.
    Creaven PJ, Allen LM, Alford DA, et al. Clinical pharmacology of isophosphamide. Clin Pharmacol Ther 1974; 16: 77–86PubMedGoogle Scholar
  65. 65.
    Genka S, Deutsch J, Stahle PL, et al. Brain and plasma pharmacokinetics and anticancer activities of cyclophosphamide and phosphoramide mustard in the rat. Cancer Chemother Pharmacol 1990; 27: 1–7PubMedGoogle Scholar
  66. 66.
    Neuwelt EA, Barnett PA, Frenkel EP. Chemotherapeutic agent permeability to normal brain and delivery to avian sarcoma virus-induced brain tumors in the rodent: observations on problems of drug delivery. Neurosurgery 1984; 14: 154–60PubMedGoogle Scholar
  67. 67.
    Arndt CA, Colvin OM, Balis FM, et al. Intrathecal administration of 4-hydroperoxycyclophosphamide in rhesus monkeys. Cancer Res 1987; 47: 5932–4PubMedGoogle Scholar
  68. 68.
    Nicolao P, Giometto B. Neurological toxicity of ifosfamide. Oncology 2003; 65 Suppl. 2: 11–6PubMedGoogle Scholar
  69. 69.
    Chabner BA, Young RC. Threshold methotrexate concentration for in vivo inhibition of DNA synthesis in normal and tumorous target tissues. J Clin Invest 1973; 52: 1804–11PubMedGoogle Scholar
  70. 70.
    Wang F, Jiang X, Lu W. Profiles of methotrexate in blood and CSF following intranasal and intravenous administration to rats. Int J Pharm 2003; 263: 1–7PubMedGoogle Scholar
  71. 71.
    Neuwelt EA, Barnett PA, Bigner DD, et al. Effects of adrenal cortical steroids and osmotic blood-brain barrier opening on methotrexate delivery to gliomas in the rodent: the factor of the blood-brain barrier. Proc Natl Acad Sci U S A 1982; 79: 4420–3PubMedGoogle Scholar
  72. 72.
    Dukic SF, Heurtaux T, Kaltenbach ML, et al. Influence of schedule of administration on methotrexate penetration in brain tumours. Eur J Cancer 2000; 36: 1578–84PubMedGoogle Scholar
  73. 73.
    Ramu A, Fusner JE, Blaschke T, et al. Probenecid inhibition of methotrexate-cerebrospinal fluid pharmacokinetics in dogs. Cancer Treat Rep 1978; 62: 1465–70PubMedGoogle Scholar
  74. 74.
    Poplack DG, Bleyer WA, Wood JH, et al. A primate model for study of methotrexate pharmacokinetics in the central nervous system. Cancer Res 1977; 37: 1982–5PubMedGoogle Scholar
  75. 75.
    Shapiro WR, Young DF, Mehta BM. Methotrexate: distribution in cerebrospinal fluid after intravenous, ventricular and lumbar injections. N Engl J Med 1975; 293: 161–6PubMedGoogle Scholar
  76. 76.
    Stephens RL, Williamson SK, Jackson WL. Methotrexate cerebrospinal fluid pharmacokinetics in a patient with lymphoma treated with methotrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine, and dexamethasone. Am J Med 1986; 81: 718–20PubMedGoogle Scholar
  77. 77.
    Tejada F, Zubrod CG. Vincristine effect on methotrexate cerebrospinal fluid concentration. Cancer Treat Rep 1979; 63: 143–5PubMedGoogle Scholar
  78. 78.
    Bode U, Magrath IT, Bleyer WA, et al. Active transport of methotrexate from cerebrospinal fluid in humans. Cancer Res 1980; 40: 2184–7PubMedGoogle Scholar
  79. 79.
    Tubiana N, Lena N, Barbet J, et al. Methotrexate-vindesine association in leukemia: pharmacokinetic study. Med Oncol Tumor Pharmacother 1985; 2: 99–102PubMedGoogle Scholar
  80. 80.
    Steiniger SC, Kreuter J, Khalansky AS, et al. Chemotherapy of glioblastoma in rats using doxorubicin-loaded nanoparticles. Int J Cancer 2004; 109: 759–67PubMedGoogle Scholar
  81. 81.
    Ohnishi T, Tamai I, Sakanaka K, et al. In vivo and in vitro evidence for ATP-dependency of P-glycoprotein-mediated efflux of doxorubicin at the blood-brain barrier. Biochem Pharmacol 1995; 49: 1541–4PubMedGoogle Scholar
  82. 82.
    Berg SL, Reid J, Godwin K, et al. Pharmacokinetics and cerebrospinal fluid penetration of daunorubicin, idarubicin, and their metabolites in the nonhuman primate model. J Pediatr Hematol Oncol 1999; 21: 26–30PubMedGoogle Scholar
  83. 83.
    Bigotte L, Olsson Y. Distribution and toxic effects of intravenously injected epirubicin on the central nervous system of the mouse. Brain 1989; 112(Pt 2): 457–69PubMedGoogle Scholar
  84. 84.
    Warren KE, Patel MC, McCully CM, et al. Effect of P-glycoprotein modulation with cyclosporin A on cerebrospinal fluid penetration of doxorubicin in non-human primates. Cancer Chemother Pharmacol 2000; 45: 207–12PubMedGoogle Scholar
  85. 85.
    Siegal T, Horowitz A, Gabizon A. Doxorubicin encapsulated in sterically stabilized liposomes for the treatment of a brain tumor model: biodistribution and therapeutic efficacy. J Neurosurg 1995; 83: 1029–37PubMedGoogle Scholar
  86. 86.
    Fundaro A, Cavalli R, Bargoni A, et al. Non-stealth and stealth solid lipid nanoparticles (SLN) carrying doxorubicin: pharmacokinetics and tissue distribution after i.V. administration to rats. Pharmacol Res 2000; 42: 337–43PubMedGoogle Scholar
  87. 87.
    Primeau AJ, Rendon A, Hedley D, et al. The distribution of the anticancer drug doxorubicin in relation to blood vessels in solid tumors. Clin Cancer Res 2005; 11: 8782–8PubMedGoogle Scholar
  88. 88.
    Morikawa N, Takeyama M, Mori T, et al. Pharmacokinetics of pirarubicin in plasma and cerebrospinal fluid. Ann Pharmacother 1998; 32: 269PubMedGoogle Scholar
  89. 89.
    Koukourakis MI, Koukouraki S, Fezoulidis I, et al. High intratumoural accumulation of stealth liposomal doxorubicin (Caelyx) in glioblastomas and in metastatic brain tumours. Br J Cancer 2000; 83: 1281–6PubMedGoogle Scholar
  90. 90.
    Zucchetti M, Boiardi A, Silvani A, et al. Distribution of daunorubicin and daunorubicinol in human glioma tumors after administration of liposomal daunorubicin. Cancer Chemother Pharmacol 1999; 44: 173–6PubMedGoogle Scholar
  91. 91.
    El-Gizawy SA, Hedaya MA. Comparative brain tissue distribution of camptothecin and topotecan in the rat. Cancer Chemother Pharmacol 1999; 43: 364–70PubMedGoogle Scholar
  92. 92.
    Straathof CS, van den Bent MJ, Loos WJ, et al. The accumulation of topotecan in 9L glioma and in brain parenchyma with and without dexamethasone administration. J Neurooncol 1999; 42: 117–22PubMedGoogle Scholar
  93. 93.
    Blaney SM, Cole DE, Balis FM, et al. Plasma and cerebrospinal fluid pharmacokinetic study of topotecan in nonhuman primates. Cancer Res 1993; 53: 725–7PubMedGoogle Scholar
  94. 94.
    Sung C, Blaney SM, Cole DE, et al. A pharmacokinetic model of topotecan clearance from plasma and cerebrospinal fluid. Cancer Res 1994; 54: 5118–22PubMedGoogle Scholar
  95. 95.
    Zamboni WC, Gajjar AJ, Mandrell TD, et al. A four-hour topotecan infusion achieves cytotoxic exposure throughout the neuraxis in the nonhuman primate model: implications for treatment of children with metastatic medulloblastoma. Clin Cancer Res 1998; 4: 2537–44PubMedGoogle Scholar
  96. 96.
    Leggas M, Adachi M, Scheffer GL, et al. Mrp4 confers resistance to topotecan and protects the brain from chemotherapy. Mol Cell Biol 2004; 24: 7612–21PubMedGoogle Scholar
  97. 97.
    Blaney SM, Takimoto C, Murry DJ, et al. Plasma and cerebrospinal fluid pharmacokinetics of 9-aminocamptothecin (9-AC), irinotecan (CPT-11), and SN-38 in nonhuman primates. Cancer Chemother Pharmacol 1998; 41: 464–8PubMedGoogle Scholar
  98. 98.
    Stewart CF, Gajjar AJ, Heideman RL, et al. Penetration of topotecan into cerebrospinal fluid after intravenous injection. Ontologie 1998; 21: 22–4Google Scholar
  99. 99.
    Zamboni WC, Luftner DI, Egorin MJ, et al. The effect of increasing topotecan infusion from 30 minutes to 4 hours on the duration of exposure in cerebrospinal fluid. Ann Oncol 2001; 12: 119–22PubMedGoogle Scholar
  100. 100.
    Broniscer A, Chintagumpala M, Fouladi M, et al. Temozolomide after radiotherapy for newly diagnosed high-grade glioma and unfavorable low-grade glioma in children. J. Neurooncol 2005; 76(3): 313–9Google Scholar
  101. 101.
    Friedman HS, Petros WP, Friedman AH, et al. Irinotecan therapy in adults with recurrent or progressive malignant glioma. J Clin Oncol 1999; 17: 1516–25PubMedGoogle Scholar
  102. 102.
    Patel M, McCully C, Godwin K, et al. Plasma and cerebrospinal fluid pharmacokinetics of intravenous temozolomide in non-human primates. J Neurooncol 2003; 61: 203–7PubMedGoogle Scholar
  103. 103.
    Reyderman L, Statkevich P, Thonoor CM, et al. Disposition and pharmacokinetics of temozolomide in rat. Xenobiotica 2004; 34: 487–500PubMedGoogle Scholar
  104. 104.
    Agarwala SS, Kirkwood JM, Gore M, et al. Temozolomide for the treatment of brain metastases associated with metastatic melanoma: a phase II study. J Clin Oncol 2004; 22: 2101–7PubMedGoogle Scholar
  105. 105.
    Christodoulou C, Bafaloukos D, Linardou H, et al. Temozolomide (TMZ) combined with cisplatin (CDDP) in patients with brain metastases from solid tumors: a Hellenic Cooperative Oncology Group (HeCOG) Phase II study. J Neurooncol 2005; 71: 61–5PubMedGoogle Scholar
  106. 106.
    Rutkowski S, Bode U, Deinlein F, et al. Treatment of early childhood medulloblastoma by postoperative chemotherapy alone. N Engl J Med 2005; 352: 978–86PubMedGoogle Scholar
  107. 107.
    Jackson Jr DV, Castle MC, Poplack DG, et al. Pharmacokinetics of vincristine in the cerebrospinal fluid of subhuman primates. Cancer Res 1980; 40: 722–4PubMedGoogle Scholar
  108. 108.
    Greig NH, Soncrant TT, Shetty HU, et al. Brain uptake and anticancer activities of vincristine and vinblastine are restricted by their low cerebrovascular permeability and binding to plasma constituents in rat. Cancer Chemother Pharmacol 1990; 26: 263–8PubMedGoogle Scholar
  109. 109.
    Cisternino S, Rousselle C, Debray M, et al. In vivo saturation of the transport of vinblastine and colchicine by P-glycoprotein at the rat blood-brain barrier. Pharm Res 2003; 20: 1607–11PubMedGoogle Scholar
  110. 110.
    Arboix M, Paz OG, Colombo T, et al. Multidrug resistance-reversing agents increase vinblastine distribution in normal tissues expressing the P-glycoprotein but do not enhance drug penetration in brain and testis. J Pharmacol Exp Ther 1997; 281: 1226–30PubMedGoogle Scholar
  111. 111.
    Castle MC, Margileth DA, Oliverio VT. Distribution and excretion of (3H)vincristine in the rat and the dog. Cancer Res 1976; 36: 3684–9PubMedGoogle Scholar
  112. 112.
    el Dareer SM, White VM, Chen FP, et al. Distribution and metabolism of vincristine in mice, rats, dogs, and monkeys. Cancer Treat Rep 1977; 61: 1269–77PubMedGoogle Scholar
  113. 113.
    Mitsunaga Y, Takanaga H, Matsuo H, et al. Effect of bioflavonoids on vincristine transport across blood-brain barrier. Eur J Pharmacol 2000; 395: 193–201PubMedGoogle Scholar
  114. 114.
    Boyle FM, Eller SL, Grossman SA. Penetration of intra-arterially administered vincristine in experimental brain tumor. Neuro-oncol 2004; 6: 300–5PubMedGoogle Scholar
  115. 115.
    Stewart DJ, Lu K, Benjamin RS, et al. Concentration of vinblastine in human intracerebral tumor and other tissues. J Neurooncol 1983; 1: 139–44PubMedGoogle Scholar
  116. 116.
    Marcucci G, Perrotti D, Caligiuri MA. Understanding the molecular basis of imatinib mesylate therapy in chronic myelogenous leukemia and the related mechanisms of resistance. Commentaryre: A. N. Mohamed, et al: the effect of imatinib mesylate on patients with Philadelphia chromosome-positive chronic myeloid leukemia with secondary chromosomal aberrations. Clin Cancer Res 9: 1333–1337, 2003. Clin Cancer Res 2003; 9: 1248–52Google Scholar
  117. 117.
    Wolff NC, Richardson JA, Egorin M, et al. The CNS is a sanctuary for leukemic cells in mice receiving imatinib mesylate for Bcr/Abl-induced leukemia. Blood 2003; 101: 5010–3PubMedGoogle Scholar
  118. 118.
    Neville K, Parise RA, Thompson P, et al. Plasma and cerebrospinal fluid pharmacokinetics of imatinib after administration to nonhuman primates. Clin Cancer Res 2004; 10: 2525–9PubMedGoogle Scholar
  119. 119.
    Dai H, Marbach P, Lemaire M, et al. Distribution of STI-571 to the brain is limited by P-glycoprotein-mediated efflux. J Pharmacol Exp Ther 2003; 304: 1085–92PubMedGoogle Scholar
  120. 120.
    Petzer AL, Gunsilius E, Hayes M, et al. Low concentrations of STI571 in the cerebrospinal fluid: a case report. Br J Haematol 2002; 117: 623–5PubMedGoogle Scholar
  121. 121.
    Druker BJ, Talpaz M, Resta DJ, et al. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med 2001; 344: 1031–7PubMedGoogle Scholar
  122. 122.
    Takayama N, Sato N, O’Brien SG, et al. Imatinib mesylate has limited activity against the central nervous system involvement of Philadelphia chromosome-positive acute lymphoblastic leukaemia due to poor penetration into cerebrospinal fluid. Br J Haematol 2002; 119: 106–8PubMedGoogle Scholar
  123. 123.
    Bornhauser M, Jenke A, Freiberg-Richter J, et al. CNS blast crisis of chronic myelogenous leukemia in a patient with a major cytogenetic response in bone marrow associated with low levels of imatinib mesylate and its N-desmethylated metabolite in cerebral spinal fluid. Ann Hematol 2004; 83: 401–2PubMedGoogle Scholar
  124. 124.
    le Coutre P, Kreuzer KA, Pursche S, et al. Pharmacokinetics and cellular uptake of imatinib and its main metabolite CGP74588. Cancer Chemother Pharmacol 2004; 53: 313–23PubMedGoogle Scholar
  125. 125.
    Strong JM, Collins JM, Lester C, et al. Pharmacokinetics of intraventricular and intravenous N,N′,N′’-triethylenethiophosphoramide (thiotepa) in rhesus monkeys and humans. Cancer Res 1986; 46: 6101–4PubMedGoogle Scholar
  126. 126.
    Heideman RL, Cole DE, Balis F, et al. Phase I and pharmacokinetic evaluation of thiotepa in the cerebrospinal fluid and plasma of pediatric patients: evidence for dose-dependent plasma clearance of thiotepa. Cancer Res 1989; 49: 736–41PubMedGoogle Scholar
  127. 127.
    Hassan M, Ehrsson H, Smedmyr B, et al. Cerebrospinal fluid and plasma concentrations of busulfan during high-dose therapy. Bone Marrow Transplant 1989; 4: 113–4PubMedGoogle Scholar
  128. 128.
    Lopez JA, Nassif E, Vannicola P, et al. Central nervous system pharmacokinetics of high-dose cytosine arabinoside. J Neurooncol 1985; 3: 119–24PubMedGoogle Scholar
  129. 129.
    Zimm S, Collins JM, Miser J, et al. Cytosine arabinoside cerebrospinal fluid kinetics. Clin Pharmacol Ther 1984; 35: 826–30PubMedGoogle Scholar
  130. 130.
    van Prooijen HC, Punt K, Muus P. Cerebrospinal fluid concentrations of cytosine arabinoside during intravenous therapy with intermediate dose: a preliminary report. Br J Haematol 1985; 59: 188–90PubMedGoogle Scholar
  131. 131.
    Lopez JA, Beardsley GP, Krikorian JG, et al. Cerebrospinal fluid and plasma pharmacokinetics of high doses of 1-beta-Darabinofuranosylcytosine in nonhuman primates. Cancer Res 1983; 43: 5190–3PubMedGoogle Scholar
  132. 132.
    Brunner V, Houyau P, Chatelut E, et al. Cerebrospinal fluid concentrations of carboplatin in a patient without blood-brain barrier disruption. Cancer Chemother Pharmacol 1995; 35: 352–3PubMedGoogle Scholar
  133. 133.
    Hande KR, Wedlund PJ, Noone RM, et al. Pharmacokinetics of high-dose etoposide (VP-16-213) administered to cancer patients. Cancer Res 1984; 44: 379–82PubMedGoogle Scholar
  134. 134.
    Fleischhack G, Jaehde U, Bode U. Pharmacokinetics following intraventricular administration of chemotherapy in patients with neoplastic meningitis. Clin Pharmacokinet 2005; 44: 1–31PubMedGoogle Scholar
  135. 135.
    Chamberlain MC. Neoplastic meningitis. J Clin Oncol 2005; 23: 3605–13PubMedGoogle Scholar
  136. 136.
    Prados MD, Schold Jr SC, Fine HA, et al. A randomized, double-blind, placebo-controlled, phase 2 study of RMP-7 in combination with carboplatin administered intravenously for the treatment of recurrent malignant glioma. Neuro-oncol 2003; 5: 96–103PubMedGoogle Scholar
  137. 137.
    Kemper EM, Verheij M, Boogerd W, et al. Improved penetration of docetaxel into the brain by co-administration of inhibitors of P-glycoprotein. Eur J Cancer 2004; 40: 1269–74PubMedGoogle Scholar
  138. 138.
    Holzmayer TA, Hilsenbeck S, Von Hoff DD, et al. Clinical correlates of MDR1 (P-glycoprotein) gene expression in ovarian and small-cell lung carcinomas. J Natl Cancer Inst 1992; 84: 1486–91PubMedGoogle Scholar
  139. 139.
    Hsia TC, Lin CC, Wang JJ, et al. Relationship between chemotherapy response of small cell lung cancer and P-glycoprotein or multidrug resistance-related protein expression. Lung 2002; 180: 173–9PubMedGoogle Scholar
  140. 140.
    Wood P, Burgess R, MacGregor A, et al. P-glycoprotein expression on acute myeloid leukaemia blast cells at diagnosis predicts response to chemotherapy and survival. Br J Haematol 1994; 87: 509–14PubMedGoogle Scholar
  141. 141.
    Tan B, Piwnica-Worms D, Ratner L. Multidrug resistance transporters and modulation. Curr Opin Oncol 2000; 12: 450–8PubMedGoogle Scholar
  142. 142.
    Ferry DR, Traunecker H, Kerr DJ. Clinical trials of P-glycoprotein reversal in solid tumours. Eur J Cancer 1996; 32A: 1070–81PubMedGoogle Scholar
  143. 143.
    Liscovitch M, Lavie Y. Cancer multidrug resistance: a review of recent drug discovery research. IDrugs 2002; 5: 349–55PubMedGoogle Scholar
  144. 144.
    Krishna R, Mayer LD. Multidrug resistance (MDR) in cancer: mechanisms, reversal using modulators of MDR and the role of MDR modulators in influencing the pharmacokinetics of anticancer drugs. Eur J Pharm Sci 2000; 11: 265–83PubMedGoogle Scholar
  145. 145.
    Zhang S, Wang X, Sagawa K, et al. Flavonoids chrysin and benzoflavone, potent breast cancer resistance protein inhibitors, have no significant effect on topotecan pharmacokinetics in rats or mdr1a/1b (-/-) mice. Drug Metab Dispos 2005; 33: 341–8PubMedGoogle Scholar
  146. 146.
    Planting AS, Sonneveld P, et al. A phase I and pharmacologic study of the MDR converter GF120918 in combination with doxorubicin in patients with advanced solid tumors. Cancer Chemother Pharmacol 2005; 55: 91–9PubMedGoogle Scholar
  147. 147.
    Malingre MM, Beijnen JH, Rosing H, et al. Co-administration of GF120918 significantly increases the systemic exposure to oral paclitaxel in cancer patients. Br J Cancer 2001; 84: 42–7PubMedGoogle Scholar
  148. 148.
    Sandler A, Gordon M, de Alwis DP, et al. A Phase I trial of a potent P-glycoprotein inhibitor, zosuquidar trihydrochloride (LY335979), administered intravenously in combination with doxorubicin in patients with advanced malignancy. Clin Cancer Res 2004; 10: 3265–72PubMedGoogle Scholar
  149. 149.
    Le LH, Moore MJ, Siu LL, et al. Phase I study of the multidrug resistance inhibitor zosuquidar administered in combination with vinorelbine in patients with advanced solid tumours. Cancer Chemother Pharmacol 2005; 56: 154–60PubMedGoogle Scholar
  150. 150.
    Gruber A, Bjorkholm M, Brinch L, et al. A phase I/II study of the MDR modulator Valspodar (PSC 833) combined with daunorubicin and cytarabine in patients with relapsed and primary refractory acute myeloid leukemia. Leuk Res 2003; 27: 323–8PubMedGoogle Scholar
  151. 151.
    Thomas H, Coley HM. Overcoming multidrug resistance in cancer: an update on the clinical strategy of inhibiting p-glycoprotein. Cancer Control 2003; 10: 159–65PubMedGoogle Scholar
  152. 152.
    Mayer U, Wagenaar E, Dorobek B, et al. Full blockade of intestinal P-glycoprotein and extensive inhibition of blood-brain barrier P-glycoprotein by oral treatment of mice with PSC833. J Clin Invest 1997; 100: 2430–6PubMedGoogle Scholar
  153. 153.
    Ward KW, Azzarano LM. Preclinical pharmacokinetic properties of the P-glycoprotein inhibitor GF120918A (HCl salt of GF120918, 9, 10-dihydro-5-methoxy-9-oxo-N-[4-[2-(l,2,3,4-tetrahydro-6,7-dimethoxy-2-i soquinolinyl)ethyl]phenyl]-4-acridine-carboxamide) in the mouse, rat, dog, and monkey. J Pharmacol Exp Ther 2004; 310: 703–9PubMedGoogle Scholar
  154. 154.
    Wallstab A, Koester M, Bohme M, et al. Selective inhibition of MDR1 P-glycoprotein-mediated transport by the acridone carboxamide derivative GG918. Br J Cancer 1999; 79: 1053–60PubMedGoogle Scholar
  155. 155.
    Breedveld P, Pluim D, Cipriani G, et al. The effect of Bcrp1 (Abcg2) on the in vivo pharmacokinetics and brain penetration of imatinib mesylate (Gleevec): implications for the use of breast cancer resistance protein and P-glycoprotein inhibitors to enable the brain penetration of imatinib in patients. Cancer Res 2005; 65: 2577–82PubMedGoogle Scholar
  156. 156.
    Salarna NN, Kelly EJ, Bui T, et al. The impact of pharmacologic and genetic knockout of P-glycoprotein on nelfinavir levels in the brain and other tissues in mice. J Pharm Sci 2005; 94: 1216–25Google Scholar
  157. 157.
    Kemper EM, van Zandbergen AE, Cleypool C, et al. Increased penetration of paclitaxel into the brain by inhibition of P-Glycoprotein. Clin Cancer Res 2003; 9: 2849–55PubMedGoogle Scholar
  158. 158.
    Barraud de LS, Comets E, Gautrand C, et al. Cerebral uptake of mefloquine enantiomers with and without the P-gp inhibitor elacridar (GF1210918) in mice. Br J Pharmacol 2004; 141: 1214–22Google Scholar
  159. 159.
    Kemper EM, Cleypool C, Boogerd W, et al. The influence of the P-glycoprotein inhibitor zosuquidar trihydrochloride (LY335979) on the brain penetration of paclitaxel in mice. Cancer Chemother Pharmacol 2004; 53: 173–8PubMedGoogle Scholar
  160. 160.
    Edwards JE, Brouwer KR, McNamara PJ. GF120918, a P-glycoprotein modulator, increases the concentration of unbound amprenavir in the central nervous system in rats. Antimicrob Agents Chemother 2002; 46: 2284–6PubMedGoogle Scholar
  161. 161.
    Savolainen J, Edwards JE, Morgan ME, et al. Effects of a P-glycoprotein inhibitor on brain and plasma concentrations of anti-human immunodeficiency virus drugs administered in combination in rats. Drug Metab Dispos 2002; 30: 479–82PubMedGoogle Scholar
  162. 162.
    Polli JW, Jarrett JL, Studenberg SD, et al. Role of P-glycoprotein on the CNS disposition of amprenavir (141W94), an HIV protease inhibitor. Pharm Res 1999; 16: 1206–12PubMedGoogle Scholar
  163. 163.
    Letrent SP, Pollack GM, Brouwer KR, et al. Effects of a potent and specific P-glycoprotein inhibitor on the blood-brain barrier distribution and antinociceptive effect of morphine in the rat. Drug Metab Dispos 1999; 27: 827–34PubMedGoogle Scholar
  164. 164.
    Dantzig AH, Law KL, Cao J, et al. Reversal of multidrug resistance by the P-glycoprotein modulator, LY335979, from the bench to the clinic. Curr Med Chem 2001; 8: 39–50PubMedGoogle Scholar
  165. 165.
    Choo EF, Leake B, Wandel C, et al. Pharmacological inhibition of P-glycoprotein transport enhances the distribution of HIV-1 protease inhibitors into brain and testes. Drug Metab Dispos 2000; 28: 655–60PubMedGoogle Scholar
  166. 166.
    Peer D, Margalit R. Fluoxetine and reversal of multidrug resistance. Cancer Lett. Epub 2005 Jul 11Google Scholar
  167. 167.
    Nakamura Y, Oka M, Soda H, et al. Gefitinib (“Iressa”, ZD1839), an epidermal growth factor receptor tyrosine kinase inhibitor, reverses breast cancer resistance protein/ABCG2-mediated drug resistance. Cancer Res 2005; 65: 1541–6PubMedGoogle Scholar
  168. 168.
    Yanase K, Tsukahara S, Asada S, et al. Gefitinib reverses breast cancer resistance protein-mediated drug resistance. Mol Cancer Ther 2004; 3: 1119–25PubMedGoogle Scholar
  169. 169.
    Kitazaki T, Oka M, Nakamura Y, et al. Gefitinib, an EGFR tyrosine kinase inhibitor, directly inhibits the function of P-glycoprotein in multidrug resistant cancer cells. Lung Cancer 2005; 49: 337–43PubMedGoogle Scholar
  170. 170.
    Stewart CF, Leggas M, Schuetz JD, et al. Gefitinib enhances the antitumor activity and oral bioavailability of irinotecan in mice. Cancer Res 2004; 64: 7491–9PubMedGoogle Scholar
  171. 171.
    Breedveld P, Beijnen JH, Schellens JH. Use of P-glycoprotein and BCRP inhibitors to improve oral bioavailability and CNS penetration of anticancer drugs. Trends Pharmacol Sci 2006 Jan; 27(1): 17–24PubMedGoogle Scholar
  172. 172.
    Venkatakrishnan K, von Moltke LL, Greenblatt DJ. Human drug metabolism and the cytochromes P450: application and relevance of in vitro models. J Clin Pharmacol 2001; 41: 1149–79PubMedGoogle Scholar
  173. 173.
    Evans WE, Relling MV. Pharmacogenomics: translating functional genomics into rational therapeutics. Science 1999; 286: 487–91PubMedGoogle Scholar
  174. 174.
    Wilkinson GR. Drug metabolism and variability among patients in drug response. N Engl J Med 2005; 352: 2211–21PubMedGoogle Scholar
  175. 175.
    Vecht CJ, Wagner GL, Wilms EB. Interactions between antiepileptic and chemotherapeutic drugs. Lancet Neurol 2003; 2: 404–9PubMedGoogle Scholar
  176. 176.
    Fetell MR, Grossman SA, Fisher JD, et al. Preirradiation paclitaxel in glioblastoma multiforme: efficacy, pharmacology, and drug interactions: new approaches to brain tumor therapy central nervous system consortium. J Clin Oncol 1997; 15: 3121–8PubMedGoogle Scholar
  177. 177.
    Baker DK, Relling MV, Pui CH, et al. Increased teniposide clearance with concomitant anticonvulsant therapy. J Clin Oncol 1992; 10: 311–5PubMedGoogle Scholar
  178. 178.
    Mross K, Bewermeier P, Kruger W, et al. Pharmacokinetics of undiluted or diluted high-dose etoposide with or without busulfan administered to patients with hematologic malignancies. J Clin Oncol 1994; 12: 1468–74PubMedGoogle Scholar
  179. 179.
    Grossman SA, Hochberg F, Fisher J, et al. Increased 9-aminocamptothecin dose requirements in patients on anticonvulsants. NABTT CNS Consortium. The New Approaches to Brain Tumor Therapy. Cancer Chemother. Pharmacol 1998; 42: 118–26Google Scholar
  180. 180.
    Zamboni WC, Gajjar AJ, Heideman RL, et al. Phenytoin alters the disposition of topotecan and N-desmethyl topotecan in a patient with medulloblastoma. Clin Cancer Res 1998; 4: 783–9PubMedGoogle Scholar
  181. 181.
    Murry DJ, Cherrick I, Salama V, et al. Influence of phenytoin on the disposition of irinotecan: a case report. J Pediatr Hematol Oncol 2002; 24: 130–3PubMedGoogle Scholar
  182. 182.
    Crews KR, Stewart CF, Jones-Wallace D, et al. Altered irinotecan pharmacokinetics in pediatric high-grade glioma patients receiving enzyme-inducing anticonvulsant therapy. Clin Cancer Res 2002; 8: 2202–9PubMedGoogle Scholar
  183. 183.
    Gajjar A, Chintagumpala MM, Bowers DC, et al. Effect of intrapatient dosage escalation of irinotecan on its pharmacokinetics in pediatric patients who have high-grade gliomas and receive enzyme-inducing anticonvulsant therapy. Cancer 2003; 97: 2374–80PubMedGoogle Scholar
  184. 184.
    Villikka K, Rivisto KT, Maenpaa H, et al. Cytochrome P450-inducing antiepileptics increase the clearance of vincristine in patients with brain tumors. Clin Pharmacol Ther 1999; 66: 589–93PubMedGoogle Scholar
  185. 185.
    Saini SP, Sonoda J, Xu L, et al. A novel constitutive androstane receptor-mediated and CYP3A-independent pathway of bile acid detoxification. Mol Pharmacol 2004; 65: 292–300PubMedGoogle Scholar
  186. 186.
    Goodwin B, Moore JT. CAR: detailing new models. Trends Pharmacol Sci 2004; 25: 437–41PubMedGoogle Scholar
  187. 187.
    Oberndorfer S, Piribauer M, Marosi C, et al. P450 enzyme inducing and non-enzyme inducing antiepileptics in glioblastoma patients treated with standard chemotherapy. J Neurooncol 2005; 72: 255–60PubMedGoogle Scholar

Copyright information

© Adis Data Information BV 2006

Authors and Affiliations

  • Susannah Motl
    • 1
  • Yanli Zhuang
    • 2
  • Christopher M. Waters
    • 3
  • Clinton F. Stewart
    • 2
  1. 1.Department of Clinical PharmacyUniversity of Tennessee Health Science CenterMemphisUSA
  2. 2.Department of Pharmaceutical SciencesSt Jude Children’s Research HospitalMemphisUSA
  3. 3.Department of PhysiologyUniversity of Tennessee Health Science CenterMemphisUSA

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