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Dose-dependent pharmacokinetics and cancer chemotherapy

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  • Non-Linear Pharmacokinetics Cancer Chemotherapy
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Summary

Dose-dependent pharmacokinetics have been reported more frequently for anticancer drugs than for other drugs, probably because anticancer drugs are studied over a wide range of doses during early evaluation and because of the increasing use of anticancer drugs at very high doses. Dose-dependent pharmacokinetics are reflected most commonly as an increase in the biological half-life of a drug and a greater than proportional increase in plasma concentration of the drug and in area under the drug concentration-time curve with increase in dose. Occasionally the rate of drug removal increases with increasing dose. These nonlinear changes in drug concentrations with dose may lead to increases in toxicity out of proportion to increases in dose. Appreciation of the possibility of dose-dependent pharmacokinetics is important in the clinical pharmacologic evaluation of new drugs, and may be essential for the design of effective therapeutic regimens.

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References

  1. Acocella G (1978) Clinical pharmacokinetics of rifampicin. Clin Pharmacokinet 3: 108–127

    Google Scholar 

  2. Ames MM, Powis G, Kuehn P (1979) Determination of pyrazoloimidazole in plasma and urine by gas-liquid chromatography using nitrogen-phosphorus detection. J Chromatogr 169: 412–415

    Google Scholar 

  3. Arnold K, Gerber N (1970) The rate of decline of diphenylhydantoin in human plasma. Clin Pharmacol Ther 11: 121–134

    Google Scholar 

  4. Ashley JJ, Levy G (1972) Inhibition of diphenylhydantoin elimination in rats by its major metabolite. Res Commun Chem Pathol Pharmacol 4: 297–304

    Google Scholar 

  5. Bachur NR, RIggs CE Jr, Green MR, Longone JJ, Vunakis HV, Levin L (1977) Plasma adriamycin and daunorubicin levels by fluorescence and radioimmunassay. Clin Pharmacol Ther 21: 70–77

    Google Scholar 

  6. Batra VK, Morrison JA, Lasseter KC, Joy VA (1979) Piperacillin kinetics. Clin Pharmacol Ther 26: 41–53

    Google Scholar 

  7. Belt RJ, Patton TF, Himmelstein KJ, Taylor S, Repta A, Sternson LA (1980) Pharmacokinetics of cis-platin in humans. (Abstract) Am Assoc Cancer Res 21: 193

    Google Scholar 

  8. Benvenuto JA, Hall SW, Farquhar P, Stewart DJ, Benjamin RS, Loo TL (1979) Pharmacokinetics and disposition of 3-deazaurdine in humans. Cancer Res 39: 349–552

    Google Scholar 

  9. Bertilsson L (1978) Clinical pharmacokinetics of carbamazepine. Clin Pharmacokinet 3: 128–143

    Google Scholar 

  10. Bjornsson TD, Levy G (1979) Pharmacokinetics of heparin. I. Studies of dose dependence in rats. J Pharmacol Exp Ther 210: 237–242

    Google Scholar 

  11. Bleyer WA (1978) The clinical pharmacology of methotrexate: New applications of an old drug. Cancer 41: 36–51

    Google Scholar 

  12. Brodie BB, Lowman JJ, Burns JJ, Lee PR, Chenkin T, Goldman A, Weiner M, Steele JM (1954) Observations on the antirheumatic and physiologic effects of phenylbutazone (Butazolidin) and some comparisons with cortisone. Am J Med 16: 181–190

    Google Scholar 

  13. Camiener GW (1967) Studies of the enzymatic deamination of cytosine arabinoside-II. Properties of the deaminase of human liver. Biochem Pharmacol 16: 1681–1689

    Google Scholar 

  14. Cano JP, Aubert C, Rigault JP, Seitz JF, Carcasone Y (1980) Pharmacokinetic studies of 5-fluorouracil (5FU) in cancer patients: Relation with clinical response and implication of measurement of 5,6-dihydro-5-fluorouracil (FUH2). (Abstract) Am Assoc Cancer Res 21: 152

    Google Scholar 

  15. Chadwick M, Silveira DM, McGarrigle PL, Liss RH, Schepis J (1979) Distribution of PALA in tissues and tumors of mice after intravenous administration. (Abstract) Am Assoc Cancer Res 20: 241

    Google Scholar 

  16. Chan KK, Cohen JL, Gross JF, Himmelstein KJ, Bateman JR, Tsu-Lee Y, Marlis AS (1978) Prediction of adriamycin disposition in cancer patients using a physiologic pharmacokinetic model. Cancer Treat Rep 42: 1161–1171

    Google Scholar 

  17. Chiuten DF, Wiernik PH, Zaharko DS, Edwards L (1980) Clinical phase I–II and pharmacokinetic study of high dose thymidine given by continuous intravenous infusion. Cancer Res 40: 818–822

    Google Scholar 

  18. Clarkson B, O'Connor A, Winston L, Hutchinson D (1964) The physiologic disposition of 5-fluorouracil and 5-fluoro-2′-deoxyuridine in man. Clin Pharmacol Ther 5: 581–610

    Google Scholar 

  19. Coffey JJ (1972) Effect of protein binding of drugs on areas under plasma concentration time curves. J Pharm Sci 61: 138–139

    Google Scholar 

  20. Cohen HJ, Jaffe N (1978) Pharmacokinetic and clinical studies of 24-h infusions of high-dose methotrexate. Cancer Chemother Pharmacol 1: 61–64

    Google Scholar 

  21. Cohen JL, Jao JY (1970) Enzymatic basis of cyclophosphamide activation by hepatic microsomes of the rat. J Pharmacol Exp Ther 174: 206–210

    Google Scholar 

  22. 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

    Google Scholar 

  23. Cooper GM, Dunning WF, Green S (1972) Role of catabolism in pyrimidine utilization for nucleic acid synthesis in vivo. Cancer Res 32: 390–394

    Google Scholar 

  24. Creasey WA, McIntosh LS, Brescia T, Odujinrin O, Aspnes GT, Murray E, Marsh JC (1976) Clinical effects and pharmacokinetics of different dosage schedules of adriamycin. Cancer Res 36: 216–221

    Google Scholar 

  25. Creaven PJ (1979) Pharmacokinetic parameters potential for and problems with the use as predictors of response to cancer chemotherapeutic agents. Bull Cancer (Paris) 66: 85–88

    Google Scholar 

  26. Creaven PJ, Allen LM, Alford DA (1975) The biovailability in man of ICRF-159, a new oral antineoplastic agent. J Pharm Pharmacol 27: 914–918

    Google Scholar 

  27. Creaven PJ, Rustum YM, Slocum HK, Mittelman A (1978) Clinical pharmacokinetics of 3-Deazauridine, a new antineoplastic agent. In: Siegenthaler W, Luthy R (eds) Current chemotherapy. American Society Microbiology, Washington, pp 1208–1210

    Google Scholar 

  28. Cunningham JL, Shen DI, Shudo I, Azarnoff DL (1977) The effect of urine pH and plasma protein binding on renal clearance of disopyramide. Clin Pharmacokinet 2: 373–383

    Google Scholar 

  29. Cysyk RL, Gormley PE, D'Anna ME, Adamson RH (1978) The disposition of 3-deazauridine in mice. Drug Metab Dispos 6: 125–132

    Google Scholar 

  30. DeConti RC, Toftness BR, Lange RC, Creasey WA (1973) Clinical and pharmacological studies with cisdiamminedichloroplatinum (II). Cancer Res 33: 1310–1315

    Google Scholar 

  31. Dedrick RL, Forrester DD, Ho DHW (1972) In vitro-in vivo correlation of drug metabolism — deamination of 1-β-d-arabinofuranosylcytosine. Biochem Pharmacol 21: 1–16

    Google Scholar 

  32. du Souich P, Lalka D, Slaughter R, Elvin AT, McLean AJ (1979) Mechanisms of nonlinear disposition kinetics of sulfamethazine. Clin Pharmacol Ther 25: 172–183

    Google Scholar 

  33. El Dareer SM, Tillery KF, Hill DH (1978) Distribution and metabolism of 2-amino-1,3,4-thiadiazole in mice, dogs, and monkeys. Cancer Treat Rep 62: 75–83

    Google Scholar 

  34. Ensminger WD, Frei E III (1977) The prevention of methotrexate toxicity by thymidine infusions in humans. Cancer Res 37: 1857–1863

    Google Scholar 

  35. Ensminger WD, Frei E III (1978) High-dose intravenous and hepatic artery infusions of thymidine. Clin Pharmacol Ther 24: 610–615

    Google Scholar 

  36. Ensminger WD, Rosowsky A, Raso V, Levin DC, Glode M, Come S, Steele G, Frei E III (1976) A clinical-pharmacologic evaluation of hepatic arterial infusions of 5-fluoro-2′-deoxyuridine and 5-fluorouracil. Cancer Res 38: 3784–3792

    Google Scholar 

  37. Erlichman C, Stron JM, Chabner BA (1980a) Application of simple competitive protein-binding assay technique to the pharmacokinetics of N-(phosphonacetyl)-l-aspartate in humans. Cancer Res 40: 1902–1906

    Google Scholar 

  38. Erlichman C, Donehower RC, Chabner BA (1980b) The practical benefits of pharmacokinetics in the use of antineoplastic agents. Cancer Chemother Pharmacol 4: 139–145

    Google Scholar 

  39. Evans GH, Shand DG (1973) Disposition of propranolol. V. Drug accumulation and steady-state concentrations during chronic oral administration in man. Clin Pharmacol Ther 14: 487–493

    Google Scholar 

  40. Finkelstein JZ, Shern J, Karon M (1970) Pharmacologic studies of tritiated cytosine arabinoside (NSC-63878) in children. Cancer Chemother Rep 54: 35–41

    Google Scholar 

  41. Fleuren HL, Verwey-van Wissen C, Van Rossum JM (1979) Dose-dependent urinary excretion of chlorthalidone. Clin Pharmacol Ther 25: 806–812

    Google Scholar 

  42. Frisk-Holmberg M, Bergkvist Y, Domeij-Nyberg B, Helstrom L, Jansson F (1979) Chloroquine serum concentration and side effects: evidence for dose-dependent kinetics. Clin Pharmacol Ther 25: 345–350

    Google Scholar 

  43. Fujita H 61971) Comparative studies on the blood level, tissue distribution, excretion and inactivation of anticancer drugs. Japanese Journal of Oncology 12: 151–162

  44. Garnick MB, Ensminger WD, Israel M (1979) A clinical-pharmacological evaluation of hepatic arterial infusion of adriamycin. Cancer Res 39: 4105–4110

    Google Scholar 

  45. Garrett ER, Hurst GH, Green JR 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: 1422–1629

    Google Scholar 

  46. Gerber N, Wagner JG (1972) Explanation of dose-dependent decline of diphenylhydantoin levels by fitting to the integrated form of the Michaelis-Menten equation. Res Commun Chem Pathol Pharmacol 3: 455–466

    Google Scholar 

  47. Gercovich FG, Praga C, Beretta G, Morganfeld M, Muchnik J, Pesce R, Ho DHW, Benjamin RS (1979) Ten-hour continuous infusion of adriamycin. (Abstract) Am Soc Clin Oncol 20: 372

    Google Scholar 

  48. Gibaldi M, Perrier D (1975) Nonlinear pharmacokinetics. In: Gibaldi M and Perrier D Pharmacokinetics. Dekker, New York, pp 215–228

    Google Scholar 

  49. Goh TS, Won KY, Lampkin B, O'Leary J, Gnarra P (1979) Evaluation of 24-hour infusion of high-dose methotrexate. Pharmacokinetics and toxicity. Cancer Chemother Pharmacol 3: 177–180

    Google Scholar 

  50. Gomeni IR, Blanchetti G, Seager R, Marselli PL (1977) Pharmacokinetics of propranolol in normal healthy volunteers. J Pharmacokinet Biopharm 5: 183–192

    Google Scholar 

  51. Gormley PE, Bull JM, LeRoy AF, Cysyk R (1979) Kinetics of cis-dichloroammineplatinum. Clin Pharmacol Ther 25: 351–357

    Google Scholar 

  52. Grochow LB, Colvin M (1979) Clinical pharmacokinetics of cyclophosphamide. Clin Pharmacol 4: 380–394

    Google Scholar 

  53. Hall SW, Salem P, Benjamin RS, Lu K, Loo TL, Murphy WK, Wharton J, Bedey GO (1978) Continuous intravenous infusion (CIVI) of cis-diamminechloroplatinum (II) (IDDP): A clinical, toxicologic and pharmacologic study. (Abstract) Am Assoc Cancer Res 19: 417

    Google Scholar 

  54. Harris PA, Gross JF (1975) Preliminary pharmacokinetic model for adriamycin (NSC-123127). Cancer Chemother Rep 59: 819–826

    Google Scholar 

  55. Henderson ES, Adamson RH, Oliverio VT (1965) The metabolic fate of tritiated methotrexate. II. Absorption and excretion in man. Cancer Res 25: 1018–1024

    Google Scholar 

  56. Hillcoat BL, McCulloch BP, Figueredo AT, Ehsan MH, Rosenfeld JM (1978) Clinical response and plasma levels of 5-fluorouracil in patients with colonic cancer treated by drug infusion. Br J Cancer 38: 719–726

    Google Scholar 

  57. Houghton GW, Richens A (1974) Rate of elimination of tracer doses of phenytoin at different steady-state serum phenytoin concentrations in epileptic patients. Br J Clin Pharmacol 1: 155–161

    Google Scholar 

  58. Howell SB, Ensminger WD, Krishnan A, Frei E III (1978) Thymidine rescue of high-dose methotrexate in humans. Cancer Res 38: 325–330

    Google Scholar 

  59. Huffman DH, Wan SH, Azarnoff DL, Hoogstraten B (1973) Pharmacokinetics of methotrexate. Clin Pharmacol Ther 14: 572–579

    Google Scholar 

  60. Ilett KF, Madson BW, Woods JD (1979) Disopyramide kinetics in patients with acute myocardial infarction. Clin Pharmacol Ther 26: 1–7

    Google Scholar 

  61. Isacoff WH, Townsend CM Jr, Eilber FR, Forster T, Morten DL, Block JB (1976) High-dose methotrexate therapy of solid tumors: Observations relating to clinical toxicity. Med Pediatr Oncol 2: 319–325

    Google Scholar 

  62. Israili ZH, Vogler WR, Mingioli ES, Pirkle JL, Smithwick RW, Goldstein JH (1976) The disposition and pharmacokinetics in humans of 5-azacytidine administerd intravenously as a bolus or by continuous infusion. Cancer Res 36: 1453–1461

    Google Scholar 

  63. Iyer VN, Szybalski W (1964) Mitomycins and porfiromycin: Chemical mechanism of activation and cross-linking of DNA. Science 145: 55–57

    Google Scholar 

  64. Jacobs SA, Stoller RG, Chabner BA, Johns DG (1976) Hydroxymethotrexate as a metabolite in human subjects and rhesus monkey receiving high-dose methotrexate. J Clin Invest 57: 534–538

    Google Scholar 

  65. Jardine I, Fenselau C, Appler M, Kan M-N, Brundrett RB, Colvin M (1978) Quantitation by gas chromatography-chemical ionization mass spectrometry of cyclophosphamide, phosphoramide mustard, and nornitrogen mustard in the plasma and urine of patients receiving cyclophosphamide therapy. Cancer Res 38: 408–415

    Google Scholar 

  66. Jayaram HM, Tyagi AK, Anandaraj S, Montgomery JA, Kelley JA, Kelley J, Adamson RH, Cooney DA (1979) Metabolites of alanosine, an antitumor antibiotic. Biochem Pharmacol 28: 3551–3566

    Google Scholar 

  67. Jenne JW, Wyze MS, Rood FS, MacDonald FM (1972) Pharmacokinetics of theophylline. Clin Pharmacol Ther 13: 349–360

    Google Scholar 

  68. King FG, Dedrick RL (1979) Pharmacokinetic model for 2-amino-1,3,4-thiadiazole in mouse, dog, and monkey. Cancer Treat Rep 63: 1939–1947

    Google Scholar 

  69. Krüger-Thiemer E (1968) Nonlinear dose-concentration relationships. Farmaco [Sci] 23: 716–721

    Google Scholar 

  70. Krüger-Thiemer E, Diller W, Bunger P (1965) Pharmacokinetic models regarding protein binding of drugs. Antimicrob Agents Chemother 1965: 183–191

    Google Scholar 

  71. Larsson H, Tropé C, Mattsson W, Orbert B (1980) Clinical pharmacokinetics of intravenously administered spirogermanium. (Abstract) Am Soc Clin Oncol 21: 334

    Google Scholar 

  72. Lee SS, Giovanella BC, Shehlin JS Jr (1977) Selective lethal effect of thymidine on human and mouse tumor cells. J Cell Physiol 92: 401–406

    Google Scholar 

  73. Leme PR, Creaven PJ, Allen LM, Berman M (1945) Kinetic model for the disposition and metabolism of moderate and high-dose methotrexate (NSC740) in man. Cancer Chemother Rep 59: 811–817

    Google Scholar 

  74. Levy G (1965) Pharmacokinetics of salicylate elimination in man. J Pharm Sci 54: 959–967

    Google Scholar 

  75. Levy G (1968) Dose-dependent effects in pharmacokinetics: In: Tedeschi DH, Tedeschi RG (eds) Importance of fundamental principles in drug evaluation. Raven Press, New York, pp 141–172

    Google Scholar 

  76. Loo TL, Luce JK, Sullivan MP, Frei E III (1968) Clinical pharmacologic observations on 6-mercaptopurine and 6-methylthiopurine ribonucleoside. Clin Pharmacol Ther 9: 180–196

    Google Scholar 

  77. Loo TL, Friedman J, Moore EC, Valdivieso M, Marti JR, Stewart P (1980) Pharmacological disposition of N-(phosphonacetyl)-l-aspartate in humans. Cancer Res 40: 86–90

    Google Scholar 

  78. Lundquist F, Wolthers H (1958) The kinetics of alcohol elimination in man. Acta Pharmacol Toxicol (Copenh) 14: 265–289

    Google Scholar 

  79. Martin BK (1965) Kinetics of elimination of drugs possessing high affinity for the plasma proteins. Nature 207: 959–960

    Google Scholar 

  80. Meffin PJ, Robert EW, Winkle RA, Harapat S, Peters FA, Harrison DC (1979) Role of concentration-dependent plasma protein binding in disopyramide disposition. J Pharmacokinet Biopharm 7: 29–46

    Google Scholar 

  81. Monjanel S, Rigault JP, Cano JP, Carcassone Y, Favre H, Baratier F (1979) High-dose methotrexate: Preliminary evaluation of a pharmacokinetic approach. Cancer Chemother Pharmacol 3: 189–196

    Google Scholar 

  82. Mukherjee KL, Heidelberger CC (1960) Studies on fluorinated pyrimidines. IX. The degradation of 5-fluorouracil-6-14C. J Biol Chem 235: 433–437

    Google Scholar 

  83. Neidhart JA, Staubus AE, Young P, King GW, Malspeis L (1980) Clinical toxic effects of 2,3-dihydro-1H-imidazol1,2Blpyrazole (IMPY) with relevant pharmacokinetic parameters. Cancer Treat Rep 64: 251–256

    Google Scholar 

  84. Nichol CA (1977) Pharmacokinetics: Selectivity of action related to physiochemical properties and kinetic patterns of anticancer drugs. Cancer 40: 519–528

    Google Scholar 

  85. Ohnuma T, Hart R, Roboz J, Andrejczuk JF (1979) Clinical and pharmacological studies with phosphonacetyl l-aspartate (PALA). (Abstract) Am Soc Clin Oncol 20: 344

    Google Scholar 

  86. Olson W, Miceli J, Weber W (1978) Dose-dependent change in sulfamethazine kinetics in rapid and slow isoniazid acetylators. Clin Pharmacol Ther 23: 204–211

    Google Scholar 

  87. O'Reilly RA, Aggeler PM, Leonge LS (1964) Studies on the coumarin anticoagulant drugs: A comparison of the pharmacodynamics of dicoumarol and warfarin in man. Thrombosis et Diathesis Haemorrhagica 11: 1–22

    Google Scholar 

  88. Patton TF, Himmelstein KJ, Belt R, Bannister SJ, Sternson LA, Repta AJ (1978) Plasma levels and urinary excretion of filterable platinum species following bolus injection and IV infusion of cis-dichlorodiammineplatinum (II) in man. Cancer Treat Rep 62: 1359–1362

    Google Scholar 

  89. Perrier D, Ashley JJ, Levy G (1973) Effect of product inhibition on kinetics of drug elimination. J Pharmacokinet Biopharm 1: 231–242

    Google Scholar 

  90. Pickup MD, Lowe JR, Leatham PA, Rhind VM, Wright V, Downie WW (1977) Dose-dependent pharmacokinetics of prednisolone. Eur J Clin Pharmacol 12: 213–219

    Google Scholar 

  91. Powis G, Ames MM (1980) Determination of 6-diazo-5-oxo-l-norleucine in plasma and urine by reversed-phase high-performance liquid chromatography of the dansyl derivative. J Chromatogr 181: 95–99

    Google Scholar 

  92. Powis G, Creagan ET, Ames MM, Kovach JS (1980a) Dose-dependent pharmacokinetic behavior and toxicity of l-alanosine in humans. (Abstract) Am Assoc Cancer Res 21: 133

    Google Scholar 

  93. Powis G, Eagan RT, Kovach JS (1980b) Pharmacokinetics and toxicity of 6-diazo-5-oxo-l-norleucine (DON) in humans. (Abstract) Am Soc Clin Oncol 21: 329

    Google Scholar 

  94. Pratt CB, Roberts D, Sharks EC, Warmath (1974) Clinical trials and pharmacokinetics of intermittent high dose methotrexate — “leucovorin rescue” for children with malignant tumors. Cancer Res 34: 3326–3331

    Google Scholar 

  95. Reich SD (1979) Mathematical modeling guide to high-dose methotrexate infusion therapy. Cancer Chemother Pharmacol 3: 25–31

    Google Scholar 

  96. Reich SD, Bachur NR, Goebel RH, Berman M (1977) A pharmacokinetic model for high-dose methotrexate infusions in man. J Pharmacokin et Biopharm 5: 421–433

    Google Scholar 

  97. Reich SD, Steinberg F, Bachur NR, Riggs CE, Goebel R, Berman M (1979) Mathematical model for adriamycin (doxorubicin) pharmacokinetics. Cancer Chemother Pharmacol 3: 125–131

    Google Scholar 

  98. Rose JQ, Jusko WJ, Nickelsen JA, Green OC (1979) Prednisolone pharmacokinetics in relation to dose. (Letter) J Pediatr 94: 1014–1015

    Google Scholar 

  99. Runkel R, Forchielli H, Sevelius M, Chaplin M, Segre E (1974) Nonlinear plasma level response to high doses of naproxen. Clin Pharmacol Ther 15: 261–266

    Google Scholar 

  100. Schoenemann PT, Yesair DW, Coffey JJ (1973) Pharmacokinetic consequences of plasma protein binding of drugs. Ann NY Acad Sci 226: 162–171

    Google Scholar 

  101. Skarin AT, Zuckerman KS, Pitman SW, Rosenthal DS, Moloney W, Frei E III, Canellos GP (1977) High-dose methotrexate with folinic acid in the treatment of advanced non-Hodgkin lymphoma including CNS involvement. Blood 50: 1039–1047

    Google Scholar 

  102. Sladek NE (1971) Metabolism of cyclophosphamide by rat hepatic microsomes. Cancer Res 31: 901–908

    Google Scholar 

  103. Speyer JL, Collins JM, Dedrick RL, Brennan MF, Buckpitt AR, Londer H, DeVita VT Jr, Myers CE (1980) Phase I and pharmacological studies of 5-fluorouracil administered intraperitoneally. Cancer Res 40: 567–572

    Google Scholar 

  104. Staubus AE, Kerr TA, Balcerzak SP, Randall G, Neidhart JA (1979) Pharmacokinetics of pyrazoloimidazole (IMPY, NSC 51143) in humans. Am Soc Clin Oncol 20: 366

    Google Scholar 

  105. Stoller RG, Jacobs SA, Drake JC, Lutz RJ, Chabner BA (1975) Pharmacokinetics of high-dose methotrexate (NSC-740). Cancer Chemother Rep 6:19–24

    Google Scholar 

  106. Stoller RG, Hande KR, Jacobs SA, Rosenberg SA, Chabner BA (1977) Use of plasma pharmacokinetics of predict and prevent methotrexate toxicity. N Engl J Med 297: 630–634

    Google Scholar 

  107. Storb R, Thomas ED (1979) Human marrow transplantation. Transplantation 28: 1–3

    Google Scholar 

  108. Tanner A, Bochner F, Caffin J, Halliday J, Powell L (1979) Dose-dependent prednisolone kinetics. Clin Pharmacol Ther 25: 571–578

    Google Scholar 

  109. Tobias JS, Weiner RS, Griffiths CT, Richman CM, Parker LM, Yankee RA (1977) Cryopreserved autologous marrow infusion following high dose cancer chemotherapy. Eur J Cancer 13: 269–277

    Google Scholar 

  110. Torkelson AR, LaBudde JA, Weikel JH Jr (1975) The metabolic fate of cyclophosphamide. Drug Metab Rev 3: 131–165

    Google Scholar 

  111. Van Prooijen HC, Vierwinden, Van Egmond J, Wessels JMC, Haan C (1976) A sensitive bio-assay for pharmacokinetic studies of cytosine arabinoside in man. Eur J Cancer 12: 899–905

    Google Scholar 

  112. Van Proojien R, Van der Kleijn E, Haanen C (1977) Pharmacokinetics of cytosine arabinoside in acute myeloid leukemia. Clin Pharmacol Ther 21: 744–750

    Google Scholar 

  113. Wagner JG (1971) Biopharmaceutics and relevant pharmacokinetics. Drug Intelligence, Hamilton, pp 302–317

    Google Scholar 

  114. Wan SH, Huffman DH, Azarnoff DL, Stephens R, Hoogstraten B (1974) Effect of route of administration on effusions on methotrexate pharmacokinetics. Cancer Res 34: 3487–3491

    Google Scholar 

  115. Weinberger M, Ginchansky E (1977) Dose-dependent kinetics of theophylline disposition in asthmatic children. J Pediatr 91: 820–824

    Google Scholar 

  116. Woodcock TM, Martin DS, Damin LAM, Kemeny NE, Young CW (1980) Combination clinical trials with thymidine and fluorouracil: A phase I and clinical pharmacologic evaluation. Cancer 45: 1135–1143

    Google Scholar 

  117. Zaharko DS, Botter BJ, Chiuten D, Wiernik PH (1979) Pharmacokinetic studies during phase I trials of high-dose thymidine infusions. Cancer Res 398: 4777–4781

    Google Scholar 

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Powis, G., Ames, M.M. & Kovach, J.S. Dose-dependent pharmacokinetics and cancer chemotherapy. Cancer Chemother. Pharmacol. 6, 1–9 (1981). https://doi.org/10.1007/BF00253003

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