Pharmaceutisch Weekblad

, Volume 14, Issue 3, pp 61–77 | Cite as

Platinum antitumour agents: A review of (bio)analysis

  • T. J. M. Hodes
  • W. J. M. Underberg
  • G. Los
  • J. H. Beijnen


This paper summarizes analytical techniques in order to get a clear picture of the ins and outs of the (bio)analysis of platinum-containing compounds. The antitumour agent cisplatin has become an indispensable drug for the cure of a variety of cancer diseases. Since its introduc-tion in the early seventies, about 2,000 related platinum complexes were designed to devoid the dose-limiting nephrotoxicity. Some of them were introduced for clinical trial, such as carboplatin and iproplatin. To investigate the mechanism of action and pharmaco-kinetic behaviour, several interesting assays for total and specific platinum determination in biological matrices have been developed, each with its own possibilities and limitations.


Chemistry, analytical Chromatography Cisplatin Electrochemistry Platinum compounds Radiochemistry Spectrometry 


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  1. 1.
    Rosenberg B, Van Camp L, Krigas T. Inhibition of cell division inEscherichia coli by electrolysis products from a platinum electrode. Nature 1965;205:698–9.PubMedGoogle Scholar
  2. 2.
    Rosenberg B, Van Camp L, Trosko JE, Mansour VH. Platinum compounds: a new class of potent antitumour agents. Nature 1969;222:385–6.PubMedGoogle Scholar
  3. 3.
    Einhorn LH, Donohue J.cis-Diamminedichloroplatinum, vinblastine and bleomycin combination chemotherapy in disseminated testicular cancer. Ann Intern Med 1977;87:293–8.PubMedGoogle Scholar
  4. 4.
    Neijt JP, Ten Bokkel Huinink WW, Van der Burg MEL, Van Oosterom AT, Vriezendorp R, Kooyman CD, et al. Randomised trial comparing two chemotherapy regimens (HEXA-CAF vs. CHAP-5) in advanced ovarian carcinoma. Lancet 1984;2:594–600.CrossRefPubMedGoogle Scholar
  5. 5.
    Kish JA, Weaver A, Jacobs J, Cummings G, Al Sarraf M. Cisplatin and 5-fluorouracil infusion in patients with recurrent and disseminated epidermoid cancer of the head and neck. Cancer 1984:53:1819–24.PubMedGoogle Scholar
  6. 6.
    Yagoda A. Cisplatin regimens in the treatment of bladder and penile cancer. In: Prestayko W, Crooke ST, Carter SK, eds. Cisplatin. Current status and new developments. New York: Academic Press, 1980:361–74.Google Scholar
  7. 7.
    Prestayko W, Crooke ST, Carter SK, eds. Cisplatin. Current status and new developments. New York: Academic Press, 1980.Google Scholar
  8. 8.
    Sleyfer DT, Meyer S, Mulder NH. Cisplatin: a review of clinical applications and renal toxicity. Pharm Weekbl [Sci] 1985;7:237–44.Google Scholar
  9. 9.
    Köpf-Maier P, Köpf H. Cytostatische Platin-Komplexe: eine unerwartete Entdeckung mit weitreichenden Konsequenzen. Naturwissenschaften 1986;73:239–47.CrossRefPubMedGoogle Scholar
  10. 10.
    Rossof AH, Slayton SE, Perlia CP. Clinical studies withcis-diamminedichloroplatinum. Cancer 1972;30:1451–6.PubMedGoogle Scholar
  11. 11.
    Walker EM, Gale GR. Methods of reduction of cisplatin nephrotoxicity. Ann Clin Lab Sci 1981;11:394–410.Google Scholar
  12. 12.
    Lee FH, Canetta R, Issell BF, Lenaz L. New platinum complexes in clinical trials. Cancer Treat Rev 1983;10:39–51.CrossRefPubMedGoogle Scholar
  13. 13.
    Wagstaff AJ, Ward, A, Benfield P, Heel RC. Carboplatin A preliminary review of its pharmacodynamic and pharmacokinetic properties and therapeutic efficacy in the treatment of cancer. Drugs 1989;37:162–90.PubMedGoogle Scholar
  14. 14.
    Vermorken JB, Ten Bokkel Huinink WW, McVie JG, Van der Vijgh WJF, Pinedo HM. Clinical experience with 1,1-diaminomethylcyclohexane(sulphato)platinum(II) (TNO-6). In: Hacker MP, Douple EB, Krahoff IH, eds. Developments in oncology. The Hague: Martinus Nijhoff Publishing, 1984;330–43.Google Scholar
  15. 15.
    Van der Vijgh WJF, Elferink F, Postma GJ, Vermorken JB, Pinedo HM. Determination of ethylenediamine-platinum(II)malonate in infusion fluids, human plasma and urine by high performance liquid chromatography. J Chromatogr 1984;310:335–42.PubMedGoogle Scholar
  16. 16.
    Anderson WK, Quagliato DA, Haugwitz RD, Narayanan VL, Wolpert-DeFilippes MK. Synthesis, physical properties, and antitumor activity of tetraplatin and related tetrachloroplatinum (IV)stereoisomers of 1,2-diaminocyclohexane. Cancer Treat Rep 1986;70:997–1002.PubMedGoogle Scholar
  17. 17.
    Riley CM, Sternson LA. Cisplatin. In: Florey K, eds. Analytical profiles of drug substances. New York: Academic Press, 1985;14:77–105.Google Scholar
  18. 18.
    Long DF, Repta AJ. Cisplatin: chemistry, distribution and biotransformation. Biopharm Drug Dispos 1981;2:1–16.PubMedGoogle Scholar
  19. 19.
    Rosenberg B. Cisplatin: its history and possible mechanisms of action. In: Prestayko AW, Crooke ST, Carter SK, eds. Cisplatin: current status and new developments. New York: Academic Press, 1980:9–20.Google Scholar
  20. 20.
    Reedijk J, Lohman PHM. Cisplatin: synthesis, antitumour activity and mechanism of action. Pharm Weekbl [Sci] 1985;7:173–80.Google Scholar
  21. 21.
    Tobe ML, Khokhar AR. Structure, activity, reactivity and solubility relationships of platinum diamine complexes. J Clin Hematol Oncol 1977;7:114–37.Google Scholar
  22. 22.
    Zwelling LA, Anderson T, Kohn KW. DNA protein and DNA interstrand cross-linking bycis- andtrans-platinum(II)-diamminedichloride in L1210 mouse leukaemia cells and its relation to cytotoxicity. Cancer Res 1979;39:365–9.PubMedGoogle Scholar
  23. 23.
    LeRoy AF, Lutz RJ, Dedrick RL, Litterst CL, Guarino AM. Pharmacokinetic study ofcis-dichlorodiammineplatinum(II) (DDP) in the beagle dog: thermodynamic and kinetic behavior of DDP in a biologic milieu. Cancer Treat Rep 1979;63:59–71.PubMedGoogle Scholar
  24. 24.
    Kristjansson, Sternson LA, Lindenbaum S. An investigation on possible oligomer formation in pharmaceutical formulations of cisplatin. Int J Pharm 1988;41:67–74.CrossRefGoogle Scholar
  25. 25.
    Macquet J, Theophanides T. DNA-platinum interactionsin vitro withtrans- andcis-Pt(NH3)2Cl2. Bioinorg Chem 1975;5:59–66.CrossRefPubMedGoogle Scholar
  26. 26.
    Rahn RO. Chromatographic analysis of the adducts formed in DNA complexed withcis-diamminedichloroplatinum(II). J Inorg Biochem 1984;21:311–21.CrossRefPubMedGoogle Scholar
  27. 27.
    Mustonen R, Takala M, Leppala S, Hemminki K. Dosedependency and stability of cisplatin binding to tissue DNA and blood proteins in rats. Carcinogenesis 1989;10:365–8.PubMedGoogle Scholar
  28. 28.
    Riley CM, Sternson LA, Repta AJ, Slyter SA. Monitoring the reactions of cisplatin with nucleotides and methionine by reversed-phase high performance liquid chromatography using cationic and anionic pairing ions. Anal Biochem 1983;130:203–14.CrossRefPubMedGoogle Scholar
  29. 29.
    Marcelis ATM, Den Hartog JHJ, Van der Marel GA, Wille G, Reedijk J. Interaction of platinum compounds with short oligodeoxynucleotides containing guanine and cytosine. Eur J Biochem 1983;135:343–9.CrossRefPubMedGoogle Scholar
  30. 30.
    Segal E, Le Pecq JB. Role of ligand exchange processes in the reaction kinetics of the antitumor drugcis-diammine-dichloroplatinum(II) with its targets. Cancer Res 1985;45:492–8.PubMedGoogle Scholar
  31. 31.
    Raudaschi-Sieber G, Lippert B. Reaction of cyanide with Pt-nucleobase complexes: preparative, spectroscopic, and structural studies. Unexpected stability of Ptthymine and Pt-uracil complexes. Inorg Chem 1985;24:2426–32.CrossRefGoogle Scholar
  32. 32.
    Sherman ES, Lippart SJ. Cisplatin. Chem Rev 1987;87:1153–81.CrossRefGoogle Scholar
  33. 33.
    Repta AJ, Long DF. Reactions of cisplatin with human plasma and plasma fractions. In: Prestayko W, Crooke ST, Carter SK, eds. Cisplatin. Current status and new developments. New York: Academic Press, 1980:285–304.Google Scholar
  34. 34.
    Gormley PE, Bull JM, LeRoy AF, Cysyk R. Kinetics ofcis-dichlorodiammineplatinum. Clin Pharmacol Ther 1979;25:351–7.PubMedGoogle Scholar
  35. 35.
    Holdener EE, Park CH, Belt RJ, Stephens RL, Hoogstraten B. Effect of mannitol and plasma on the cytotoxicity of cisplatin. Eur J Cancer Clin Oncol 1983;19:515–8.CrossRefPubMedGoogle Scholar
  36. 36.
    Van der Vijgh WJF, Klein I. Protein binding of five platinum compounds: comparison of two ultrafiltration systems. Cancer Chemother Pharmacol 1986;18:129–32.CrossRefPubMedGoogle Scholar
  37. 37.
    Daley-Yates PT, McBrien DCH. Cisplatin metabolites: a method for their separation and for measurement of their renal clearancein vivo. Biochem Pharmacol 1983;32:181–4.CrossRefPubMedGoogle Scholar
  38. 38.
    Tjaden UR, De Bruijn EA. Chromatographic analysis of anticancer drugs. J Chromatogr 1990;531:235–94.PubMedGoogle Scholar
  39. 39.
    Riley CM. Bioanalysis of cisplatin analogues — a selective review. J Pharm Biomed Anal 1988;6:669–76.CrossRefGoogle Scholar
  40. 40.
    Litterst CL, Gram TE, Dedrick RL, Le Roy AF, Guarino AM. Distribution and disposition of platinum following intravenous administration ofcis-diamminedichloroplatinum(II) (NSC 119875) to dogs. Cancer Res 1976;36:2340–4.PubMedGoogle Scholar
  41. 41.
    Wilkinson BW, Toth-Allan J. Neutron activation analysis using daughter activity. Nucl Technol 1972;13:103–5.Google Scholar
  42. 42.
    Lange RC, Spencer RP, Harder HC. Synthesis and distribution of a radiolabeled antitumor agent:cis-diamminedichloroplatinum(II). J Nucl Med 1972;13:328–30.PubMedGoogle Scholar
  43. 43.
    Wolf W, Manake RC, Leh FKV. The use of radionuclides of platinum. J Clin Hematol Oncol 1977;7:741–59.Google Scholar
  44. 44.
    Safirstein R, Miller P, Guttenplan JB. Uptake and metabolism of cisplatin by rat kidney. Kidney Int 1984;25:753–8.PubMedGoogle Scholar
  45. 45.
    Lange RC, Spencer RP, Harder HC. The antitumor agentcis-Pt(NH3)2Cl2: distribution studies and dose calculations for193mPt and195mPt. J Nucl Med 1973;14:191–5.PubMedGoogle Scholar
  46. 46.
    DeSimone PA, Yancey RS, Coupal JJ, Butts JD, Hoeschele JD. Effect of a forced diuresis on the distribution and excretion (via urine and bile) of195mPlatinum when given as195mPlatinumcis-dichlorodiammineplatinum(II). Cancer Treat Rep 1979;63:951–60.PubMedGoogle Scholar
  47. 47.
    Smith PHS, Taylor DM. Distribution and retention of the antitumour agent195mPt-cis-dichlorodiammineplatinum(II) in man. J Nucl Med 1974;15:349–51.PubMedGoogle Scholar
  48. 48.
    Litterst CL, Magin R. Alterations in plasma pharmacokinetics of cisplatin in tumor-bearing rats. Cancer Chemother Pharmacol 1988;22:1–4.CrossRefPubMedGoogle Scholar
  49. 49.
    DeConti RC, Toftness BR, Lange RC, Creasey WA. Clinical and pharmacological studies withcis-diamminedichloroplatinum(II). Cancer Res 1973;33:1310–5.PubMedGoogle Scholar
  50. 50.
    Bourne DWA, Triplett JW, Hayden TL, DeSimone PA, Hoeschele JD. Pharmacokinetics ofcis-dichlorodiammineplatinum(II) in rats using an external loopeigenfunction expansion technique. J Pharm Sci 1979;68:1571–2.PubMedGoogle Scholar
  51. 51.
    Cole WC, Wolf W. Renal toxicity studies of proteinbound platinum(cis). Chem Biol Interact 1981;35:341–8.CrossRefPubMedGoogle Scholar
  52. 52.
    Bernard P, Desplances D, Macquet JP, Simon J. Cancer Treat Rep 1983;67:457–66.PubMedGoogle Scholar
  53. 53.
    Ewen C, Perera A, Hendry JH, McAuliffe CA, Sharma H, Fox BW. An autoradiographic study of the intrarenal localisation and retention of cisplatin, iproplatin and paraplatin. Cancer Chemother Pharmacol 1988;22:241–5.CrossRefPubMedGoogle Scholar
  54. 54.
    Ehmann WD, Yates SW. Nuclear and radiochemical analysis. Anal Chem 1988;60:42R-62R.CrossRefGoogle Scholar
  55. 55.
    Taskaere E, Karaivanova M, Grigorov T. Determination of platinum and gold in biological materials by neutron activation analysis. J Radioanal Nucl Chem 1988;120:75–82.Google Scholar
  56. 56.
    Sykes TR, Stephens-Newsham LG, Apps MJ, Noujaim AA. Assay of platinum and gold in biological material by neutron activation analysis. J Radioanal Chem 1982;69:441–52.Google Scholar
  57. 57.
    Kucera J, Drobnik J. Determination of platinum in urine and serum after the administration of cisplatin by neutron activation analysis. J Radioanal Chem 1982;75:71–80.Google Scholar
  58. 58.
    Tjioe PS, Volkers KJ, Kroon JJ, De Goeij JJM, The SK. Determination of gold and platinum traces in biological materials as a part of a multi-element radiochemical activation analysis system. Int J Environ Anal Chem 1984;17:13–24.PubMedGoogle Scholar
  59. 59.
    Esposito M, Collecchi P, Oddone M, Meloni S. Platinum assay by neutron activation analysis and atomic absorption spectroscopy in cisplatin pregnant mice. J Radioanal Nucl Chem 1987;113:437–43.Google Scholar
  60. 60.
    Haeberlin ST, Lux F, Karl J, Spruss T, Schonenberger H. Determination of platinum and biologically important trace elements in structure — activity relationship studies on platinum-containing anti-cancer drugs. Special procedures for removing32p as well as for the estimation of99Mo and199Au. J Radioanal Nucl Chem 1987;113:461–7.Google Scholar
  61. 61.
    Miller RG, Doerger JU. Determination of platinum and palladium in biological samples. At Absorp Newslett 1975;14:66–7.Google Scholar
  62. 62.
    Pera MF, Harder HC. Analysis for platinum in biological material by flameless atomic absorption spectrometry. Clin Chem 1977;23:1245–9.PubMedGoogle Scholar
  63. 63.
    Macquet JP, Theophanides T. Atomic absorption and relation between stability andcis-trans isomerism in platinum complexes. At Absorp Newslett 1975;14:23–5.Google Scholar
  64. 64.
    Kroïn JS, Penn RD. Intracerebral chemotherapy: chronic micro-infusion of cisplatin. Neurosurgery 1982;10:349–54.PubMedGoogle Scholar
  65. 65.
    Le Roy AF, Wehling ML, Sponseller HL, Friauf WS, Solomon RE, Dedrick RL, et al. Analysis of platinum in biological materials by flameless atomic absorption spectrophotometry. Biochem Med 1977;18:184–91.CrossRefPubMedGoogle Scholar
  66. 66.
    Appenroth D, Winnefeld K, Braunlich H. Nephrotoxicity and pharmacokinetics of cisplatinum in young and adult rats. Biomed Biochem Acta 1988;47:791–7.Google Scholar
  67. 67.
    Vermorken JB, Van der Vijgh WJF, Klein I, Hart AAM, Gall HE, Pinedo HM. Pharmacokinetics of free and total platinum species after short-term infusion of cisplatin. Cancer Treat Rep 1984;68:505–13.PubMedGoogle Scholar
  68. 68.
    Vermorken JB, Van der Vijgh WJF, Klein I, Gall HE, Van Groeningen CJ, Hart AAM, et al. Pharmacokinetics of free and total platinum species after rapid and prolonged infusions of cisplatin. Clin Pharmacol Ther 1986;39:136–44.PubMedGoogle Scholar
  69. 69.
    Denniston ML, Sternson LA, Repta AJ. Analysis of total platinum derived from cisplatin in tissue. Anal Lett 1981;14:451–62.Google Scholar
  70. 70.
    Bannister SJ, Chang Y, Sternson LA, Repta AJ. Atomic absorption spectrophotometry of free circulating platinum species in plasma derived fromcis-dichlorodiammine-platinum(II). Clin Chem 1978;24:877–80.PubMedGoogle Scholar
  71. 71.
    Belt RJ, Himmelstein KJ, Patton TF, Bannister SJ, Sternson LA, Repta AJ. Pharmacokinetics of nonprotein-bound platinum species following administration ofcis-dichlorodiammineplatinum(II). Cancer Treat Rep 1979;63:1515–21.PubMedGoogle Scholar
  72. 72.
    Patton TF, Himmelstein KJ, Belt R, Bannister SJ, Sternson LA, Repta AJ. Plasma levels and urinary excretion of filterable platinum species following bolus injection and iv infusion ofcis-dichlorodiammineplatinum(II) in man. Cancer Treat Rep 1978;62:1359–62.PubMedGoogle Scholar
  73. 73.
    Hull DA, Muhammad N, Lanese JG, Reich SD, Finkelstein TT, Fandrich S. Determination of platinum in serum and ultrafiltrate by flameless atomic absorption spectrophotometry. J Pharm Sci 1981;70:500–2.PubMedGoogle Scholar
  74. 74.
    Priesner D, Sternson LA, Repta AJ. Analysis of total platinum in tissue samples by flameless atomic absorption spectrophotometry. Elimination of the need for sample digestion. Anal Lett 1981;14:1255–68.Google Scholar
  75. 75.
    Curt GA, Grygiel JJ, Corden BJ, Ozols RF, Weiss RB, Tell DT, et al. A phase I and pharmacokinetic study of diamminecyclobutane-dicarboxylatoplatinum (NSC 241240). Cancer Res 1983;43:4470–3.PubMedGoogle Scholar
  76. 76.
    Rahman A, Roh JK, Wolpert-DeFilippes MK, Goldin A, Venditti JM, Woolley PV. Therapeutic and pharmacological studies of tetrachloro(d,l-trans)1,2-diaminocyclohexane platinum(IV) (Tetraplatin), a new platinum analogue. Cancer Res 1988;48:1745–52.PubMedGoogle Scholar
  77. 77.
    Los G, Reuvekamp M, Bosnie N, De Graaf PW, McVie JG. Intraperitoneal tumor growth and chemotherapy in a rat model. Eur J Clin Oncol 1989;25:1857–63.CrossRefGoogle Scholar
  78. 78.
    Nagel JD, Los G, Begg AC, McVie JG. A new intraperitoneal tumor model in the rat. Cancer Chemother Pharmacol 1990;27:121–4.CrossRefPubMedGoogle Scholar
  79. 79.
    Casper ES, Kelsen DP, Alcock NW, Young CW. Platinum concentrations in bile and plasma following rapid and 6-hour infusions ofcis-dichloro-diammineplatinum(II). Cancer Treat Rep 1979;63:2023–5.PubMedGoogle Scholar
  80. 80.
    Gouyette A, Lemoine R, Adhemar JP, Kleinknecht D, Man N-K, Droz JP, et al. Kinetics of cisplatin in an anuric patient undergoing hemofiltration. Cancer Treat Rep 1981;65:665–8.PubMedGoogle Scholar
  81. 81.
    Gullo JJ, Litterst CL, Maguire PJ, Sikic BI, Hoth DF, Woolley PV. Pharmacokinetics and protein binding ofcis-dichlorodiammine platinum(II) administered as a one hour or as a twenty hour infusion. Cancer Chemother Pharmacol 1980;5:21–6.CrossRefPubMedGoogle Scholar
  82. 82.
    Ostrow S, Egorin MJ, Hahn D, Markus S, Aisner J, Chang P, et al. High-dose cisplatin therapy using mannitol versus furosemide diuresis: comparative pharmacokinetics and toxicity. Cancer Treat Rep 1981;65:73–8.Google Scholar
  83. 83.
    Daley-Yates PT, McBrien DCH. Cisplatin metabolites in plasma, a study of their pharmacokinetics and importance in the nephrotoxic and antitumor activity of cisplatin. Biochem Pharmacol 1984;33:3063–70.CrossRefPubMedGoogle Scholar
  84. 84.
    Jacobs C, Kalman SM, Tretton N, Weiner MW. Renal handling ofcis-diammmedichloroplatinum(II). Cancer Treat Rep 1980;64:1223–6.PubMedGoogle Scholar
  85. 85.
    Ward JM, Grabin ME, Le Roy AF, Young DM. Modification of the renal toxicity ofcis-dichlorodiammineplatinum(II) with furosemide in male F344 rats. Cancer Treat Rep 1977;61:375–9.PubMedGoogle Scholar
  86. 86.
    Dumas M, De Gislain C, D'Athis P, Chadoint-Noudeau V, Escousse A, Guerrin J, et al. Evaluation of the effect of furosemide on ultrafilterable platinum kinetics in patients treated withcis-diamminedichloroplatinum. Cancer Chemother Pharmacol 1989;23:37–40.CrossRefPubMedGoogle Scholar
  87. 87.
    Cano JP, Catalin J, Bues-Charbit M. Platinum determination in plasma and urine by flameless atomic absorption spectrophotometry. J Appl Toxicol 1982;2:33–8.Google Scholar
  88. 88.
    Frick GA, Ballentine R, Driever CW, Kramer WG. Renal excretion of high dosecis-dichlorodiammineplatinum(II) administered with hydration and mannitol diuresis. Cancer Treat Rep 1979;63:13–6.PubMedGoogle Scholar
  89. 89.
    Vermorken JB, Van der Vijgh WJF, Pinedo HM. Pharmacokinetic evidence for an enterohepatic circulation in a patient treated withcis-dichlorodiammineplatinum(II). Res Commun Chem Pathol Pharmacol 1980;28:319–28.PubMedGoogle Scholar
  90. 90.
    Vermorken JB, Van der Vijgh WJF, Klein I, Gall HE, Pinedo HM. Pharmacokinetics of free platinum species following rapid, 3-hr and 24-hr infusions ofcis-diamminedichloro-platinum(II) and its therapeutic implications. Eur J Cancer Clin Oncol 1982;18:1069–74.CrossRefPubMedGoogle Scholar
  91. 91.
    Smeyers-Verbeke J, Detaevernier MR, Denis L, Massart DL. The determination of platinum in biological fluid by means of graphite furnace atomic absorption spectrometry. Clin Chim Acta 1981;113:329–33CrossRefPubMedGoogle Scholar
  92. 92.
    Gormley PE, Gamgji D, Wood JH, Poplack DG. Pharmacokinetic study of cerebrospinal fluid penetration ofcis-diammine-dichloroplatinum (II). Cancer Chemother Pharmacol 1981;5:257–60.CrossRefPubMedGoogle Scholar
  93. 93.
    Dominici C, Alimonti A, Caroli S, Petrucci F, Castello MA. Chemotherapeutic agent cisplatin monitoring in biological fluids by means of inductively-coupled plasma emission spectrometry (ICP-AES). Clin Chim Acta 1986;158:207–15.CrossRefPubMedGoogle Scholar
  94. 94.
    Boumans PWJM. Inductively coupled plasma. In: Boumans PWJM, ed. Inductively coupled plasma emission spectroscopy. New York: John Wiley & Sons, 1987:69–99.Google Scholar
  95. 95.
    Winge RK, Fassel VA, Peterson VJ, Floyd MA. Inductively coupled plasma emission spectroscopy. Amsterdam: Elsevier, 1985:277.Google Scholar
  96. 96.
    Alimonti A, Petrucci F, Dominici C, Caroli S. Determination of Pt in biological samples by inductively coupled plasma atomic emission spectrometry (ICPAES) with electrothermal vaporization (ETV). J Trace Elem Electrolytes Health Dis 1987;1:79–83.PubMedGoogle Scholar
  97. 97.
    Belliveau JF, Matook GM, O'Leary GP, Cummings FJ, Hillstrom M, Calabresci P. Microanalysis for platinum and magnesium in body fluids and brain tissue of mice treated with cisplatinum using graphite filament plasma emission spectroscopy. Anal Lett 1986;19:135–49.Google Scholar
  98. 98.
    Lo FB, Arai DK, Nazar MA. Determination of platinum in urine by inductively coupled plasma atomic emission spectrometry. J Anal Toxicol 1987;11:242–6.PubMedGoogle Scholar
  99. 99.
    McLoughlin S, Bowdler D, Roberts NB. Measurement of platinum in plasma and urine by direct current plasma atomic emission spectrometry. J Anal At Spectrom 1988;3:273–8.CrossRefGoogle Scholar
  100. 100.
    Van Hennik MB, Van der Vijgh WJF, Klein I, Vermorken JB, Pinedo HM. Human pharmacokinetics of carboplatin after oral administration. Cancer Chemother Pharmacol 1989;23:126–7.CrossRefPubMedGoogle Scholar
  101. 101.
    Bannister SJ, Sternson LA, Repta AJ, James GW. Measurement of free-circulatingcis-dichlorodiammineplatinum(II) in plasma. Clin Chem 1977;23:2258–62.PubMedGoogle Scholar
  102. 102.
    Seifert W, Caprioli R, Benjamin R, Hester JP. Energy dispersive X-ray fluorescence determination of platinum in plasma, urine & cerebrospinal fluid of patients administeredcis-diamminedichloroplatinum(II) (DPP). Proc Am Assoc Cancer Res 1979;20:168.Google Scholar
  103. 103.
    Stewart DJ, Leavens M, Maor M, Feun L, Luna M, Bonura J, et al. Human central nervous system distribution ofcis-diamminedichloroplatinum and use as a radiosensitizer in malignant brain tumors. Cancer Res 1982;42:2474–9.PubMedGoogle Scholar
  104. 104.
    Sargentini-Maier ML, Maier EA, Ruch C, Dufour P, Oberling F, Le Roy MJF. Simultaneous determination of Pt and essential trace elements in plasma by energy dispersive X-ray fluorescence (EDXRF). J Trace Elem Electr Health Dis 1987;1:99–105.Google Scholar
  105. 105.
    Calvert AH, Harland SJ, Newell DR, Siddik ZH, Jones AC, McElwain TJ, et al. Early clinical studies withcis-diammine-1,1-cyclobutane dicarboxylate platinum II. Cancer Chemother Pharmacol 1982;9:140–7.CrossRefPubMedGoogle Scholar
  106. 106.
    Jonson R, Mattson S, Unsgaard B.In vivo determination of platinum concentration aftercis-platinum therapy of testicular carcinoma. In: Ishigami J, ed. Recent Advances in Chemotherapy. Proceedings of an International Congress on Chemotherapy, Anticancer Section. Tokyo: Tokyo University Press, 1985;14:12222–4.Google Scholar
  107. 107.
    Thompson BC, Rayburn LA, Holaday SR. Detection of platinum in brain tissue by PIXE. IEEE Trans Nucl Sci 1981;NS28:1396–7.Google Scholar
  108. 108.
    Dikhoff TGMH, Van der Heide JA, McVie JG. Topographic PIXE analysis of platinum levels in kidney slices from cisplatin treated patients. Nucl Instrument Methods Phys Res 1985;B10/11:639–42.Google Scholar
  109. 109.
    Los G, Mutsaers PHA, Van der Vijgh WJF, Baldew GS, De Graaf PW, McVie JG. Direct diffusion ofcis-diamminedichloroplatinum(II) in intraperitoneal rat tumours after intraperitoneal chemotherapy; a comparison with systemic chemotherapy. Cancer Res 1986;49:3380–4.Google Scholar
  110. 110.
    Los G, Mutsaers PHA, Lenglet WJM, Baldew GS, McVie JG. Platinum distribution in intraperitoneal tumors after intraperitoneal cisplatin treatment. Cancer Chemother Pharmacol 1990;25:389–94.CrossRefPubMedGoogle Scholar
  111. 111.
    Johansson TB, Akselsson R, Johansson SAE. X-ray analysis: elemental trace analysis at the 10−12g level. Nucl Instrument Methods 1970;84:141–4.CrossRefGoogle Scholar
  112. 112.
    Dikhoff TGMH, Prins M, Hoffman LJB. Target preparation of biological specimens for SPIXE measurements. Nucl Instrument Methods 1982;97:129–33.CrossRefGoogle Scholar
  113. 113.
    Los G, McVie JG. Experimental and clinical status of intraperitoneal chemotherapy. Eur J Cancer 1990;26:755–62.PubMedGoogle Scholar
  114. 114.
    Los G, Mutsaers PHA, Dubbelman R, van der Hoeven CJ, McVie JG. Platinum distribution in rat and human peritoneal autopsy tumor samples after treatment with cDPP and CBDCA. In: Lobbezoo MW, Winograd B, eds. Proc Sixth NCI/EORTC Symposium on new drugs in cancer therapy; 1989 March 7–10; Amsterdam. Amsterdam: NCI/EORTC, 1989: Abstract 220.Google Scholar
  115. 115.
    Riley CM, Sternson LA. Recent advances in the clinical analysis of cisplatin. Pharm Int 1984;5:15–9.Google Scholar
  116. 116.
    Kizu R, Higashi S, Miyazaki M. A method for the determiningcis-dichlorodiammineplatinum(II) in plasma and urine by high performance liquid chromatography with direct ultraviolet detection. Chem Pharm Bull 1985;33:4614–7.PubMedGoogle Scholar
  117. 117.
    Kizu R, Hayakawa K, Miyazaki M. HPLC determination ofcis-diamminedichloroplatinum(II) in plasma and urine with UV detection and column-switching. Biomed Chrom 1989;3:14–9.CrossRefGoogle Scholar
  118. 118.
    Bannister SJ, Sternson LA, Repta AJ. Urine analysis of platinum species derived fromcis-dichlorodiammineplatinum(II) by high-performance liquid chromatography following derivatization with sodium diethyldithiocarbamate. J Chromatogr 1979;173:333–42.CrossRefPubMedGoogle Scholar
  119. 119.
    Monteith DK, Connor TH, Benvenuto JA, Fairchild EJ, Theiss JC. Stability and inactivation of mutagenic drugs and their metabolites in the urine of patients administered antineoplastic therapy. Environ Mol Mutagen 1987;10:341–56.PubMedGoogle Scholar
  120. 120.
    Andrews PA, Wung WE, Howell SB. A high performance liquid chromatographic assay with improved selectivity for cisplatin and active platinum(II) complexes in plasma ultrafiltrate. Anal Biochem 1984;143:46–56.CrossRefPubMedGoogle Scholar
  121. 121.
    Reece PA, McCall JT, Powis G, Richardson RL. Sensitive high-performance liquid chromatographic assay for platinum in plasma ultrafiltrate. J Chromatogr 1984;306:417–23.PubMedGoogle Scholar
  122. 122.
    Drummer OH, Proudfoot A, Howes L, Louis WJ. High performance liquid chromatographic determination of platinum(II) in plasma ultrafiltrate and urine: comparison with a flameless atomic absorption spectrometric method. Clin Chim Acta 1984;136:65–74.CrossRefPubMedGoogle Scholar
  123. 123.
    Borch RF, Markovitz JH, Pleasanta ME. A new method for the HPLC analysis of Pt(II) in urine. Anal Lett 1979;12:917–26.Google Scholar
  124. 124.
    Inagaki K, Yonehara S, Kidani Y. Direct determination ofcis-dichlorodiammineplatinum(II) in urine by derivative spectroscopy. Chem Pharm Bull 1985;33:3369–74.PubMedGoogle Scholar
  125. 125.
    Hussain AA, Haddadin M, Iga K. Reaction ofcis-platinum with sodium bisulfite. J Pharm Sci 1980;69:364–5.PubMedGoogle Scholar
  126. 126.
    Sternson LA, Marsh KC, Bannister SJ, Repta AJ. Detection systems for assay of antineoplastic platinum complexes. Anal Proc 1983;20:366–8.Google Scholar
  127. 127.
    Gooijer C, Veltkamp AC, Baumann RA, Velthorst NH, Frei RW, Van der Vijgh WJF. Analysis of platinum complexes by liquid chromatography with quenched phosphorescence detection. J Chromatogr 1984;312:337–44.CrossRefGoogle Scholar
  128. 128.
    Elferink F, Van der Vijgh WJF, Pinedo HM. On-line differential pulse polarographic detection of carboplatin in biological samples after chromatographic separation. Anal Chem 1986;58:2293–6.CrossRefPubMedGoogle Scholar
  129. 129.
    Newell DR, Siddik ZH, Harrap KR. HPLC analysis of cisplatin analogues in biological fluids. Methodol Surv Biochem Anal 1984;14:145–53.Google Scholar
  130. 130.
    Gaver RC, Deeb G. High-performance liquid chromatographic procedures for the analysis of carboplatin in human plasma and urine. Cancer Chemother Pharmacol 1986;16:201–6.CrossRefPubMedGoogle Scholar
  131. 131.
    Marsh KC, Sternson LA, Repta AJ. Post-column reaction detector for platinum(II) antineoplastic agents. Anal Chem 1984;56:491–7.CrossRefPubMedGoogle Scholar
  132. 132.
    Llopis JF, Colom F. Platinum In: Bard AJ, ed. Encyclopedia of electrochemistry of the elements. New York: Marcel Dekker, 1976:169–219.Google Scholar
  133. 133.
    Vrana O, Kleinwachter V, Brabec V. Determination of platinum in urine by differential pulse polarography. Talanta 1983;30:288–90.CrossRefGoogle Scholar
  134. 134.
    Brabec V, Vrana O, Kleinwachter V. Determination of platinum in biological material by differential pulse polarography: analysis in urine, plasma and tissue following sample combustion. Collect Czech Chem Commun 1983;48:2903–8.Google Scholar
  135. 135.
    Bartosek I, Cattaneo MT, Grasselli G, Guaitani A, Urso R, Zucca A, et al. Polarographic assay of submicrogram quantities ofcis-dichlorodiamineplatinum(II) in biological samples. Tumori 1983;69:741–59.Google Scholar
  136. 136.
    Shearan P, Smyth MR. Comparison of voltammetric and graphite furnace atomic absorption spectrometric methods for the direct determination of inorganic platinum in urine. Analyst 1988;113:609–12.CrossRefPubMedGoogle Scholar
  137. 137.
    Schmid GM, Atherton DR. Voltammetric determination of platinum from aqueous solutions and from urine. Anal Chem 1986;58:1956–9.CrossRefPubMedGoogle Scholar
  138. 138.
    Wang J, Peng T, Lin MS. Voltammetric measurement ofcis-dichlorodiammineplatinum(II) following interfacial accumulation at mercury electrodes. Bioelectrochem Bioenerg 1986;16:395–406.CrossRefGoogle Scholar
  139. 139.
    Zhao Z, Freiser H. Differential pulse polarographic determination of trace levels of platinum. Anal Chem 1986;58:1498–501.CrossRefGoogle Scholar
  140. 140.
    Mason RW, Hogg SJ, Edwards IR. Distribution of Pt in the urine and kidney of the cisplatin treated rat. Toxicology 1986;38:219–26.CrossRefPubMedGoogle Scholar
  141. 141.
    Elferink F, Leeuwenkamp OR, Pinedo HM, Van der Vijgh WJF. Electrochemistry of platinum complexes. Part I. Polarographic reduction mechanism with reference to electrochemical detection. J Electroanal Chem 1987;238:297–313.CrossRefGoogle Scholar
  142. 142.
    Bannister SJ, Sternson LA, Repta AJ. Evaluation of reductive amperometric detection in the liquid chromatographic determination of antineoplastic platinum complexes. J Chromatogr 1983;273:301–18.PubMedGoogle Scholar
  143. 143.
    Cushing JP, Hubbard AT. Study of the kinetics of electrochemical reactions by thin-layer voltammetry. J Electroanal Chem Interfac Electrochem 1969;23:183–203.CrossRefGoogle Scholar
  144. 144.
    Richmond WN, Baldwin RP. Chloride-assisted electrochemical detection ofcis-dichlorodiammineplatinum(II) after liquid chromatography. Anal Chim Acta 1983;154:133–42.CrossRefGoogle Scholar
  145. 145.
    Krull IS, Ding XD, Braverman S, Selavka C, Hochberg F, Sternson LA. Trace analysis forcis-platinum anti-cancer drugs via LCEC. J Chromatogr Sci 1983;21:166–73.PubMedGoogle Scholar
  146. 146.
    Ding XD, Krull IS. Dual electrode liquid chromatography-electrochemical detection (LCEC) for platinum-derived cancer chemotherapy agents. J Liq Chromatogr 1983;6:2173–94.Google Scholar
  147. 147.
    Krull IS, Ding XD, Selavka C, Hochberg F. HPLCelectrochemical determination of cisplatinum anticancer drugs. Meth Surv Biochem Anal 194;14:139–44.Google Scholar
  148. 148.
    Mebsout F, Kauffmann JM, Patriarche GJ. Redox behaviour of anti-tumor platinum(II) compounds (carboplatin) at solid electrodes. J Pharm Biomed Anal 1987;5:223–31.CrossRefGoogle Scholar
  149. 149.
    Vrana O, Brabec V. Electrochemical analysis of antitumour platinum drugs and their complexes with DNA. Bioelectrochem Bioenerg 1988;19:145–60.CrossRefGoogle Scholar
  150. 150.
    Van der Vijgh WJF, Van der Lee HBJ, Postma GJ, Pinedo HM. High sensitive differential pulse amperometric detection of second generation anti-tumor platinum compounds in HPLC eluents. Chromatographia 1983;17:333–6.Google Scholar
  151. 151.
    Elferink F, Van der Vijgh WJF, Pinedo HM. Analysis of antitumor [1,1-bis(aminomethyl)cyclohexane]platinum(II) complexes derived from spiroplatin by highperformance liquid chromatography with differential pulse amperometric detection. J Chromatogr 1985;320:379–92.CrossRefPubMedGoogle Scholar
  152. 152.
    Alexander PW, Hoh R, Smythe LE. Trace determination of platinum: a catalytic method using pulse polarography. Talanta 1977;24:543–8.CrossRefGoogle Scholar
  153. 153.
    Treskes M, De Jong J, Leeuwenkamp OR, Van der Vijgh WJF. Sensitive determination of cisplatin in body fluids with HPLC and on-line reductive electrochemical detection. J Liq Chromatogr 1990;13:1321–38.Google Scholar
  154. 154.
    Elferink F. Analysis, electrochemistry and pharmacokinetics of second generation platinum compounds [dissertation]. Amsterdam: Free Univ, 1987.Google Scholar
  155. 155.
    Riley CM, Sternson LA, Repta AJ. Assessment of cisplatin reactivity with peptides and proteins using reverse-phase high performance liquid chromatography and flameless atomic absorption spectroscopy. Anal Biochem 1982;124:167–79.CrossRefPubMedGoogle Scholar
  156. 156.
    Mariani EP, Southard BJ, Woolever JT, Erlich RH, Granatek AP. Physical compatibility and chemical stability of cisplatin in various diluents and in largevolume parenteral solutions. In: Prestayko AW, Crooke ST, Carter SK, eds. Cisplatin. Current status and new developments. New York: Academic Press, 1980:305–16.Google Scholar
  157. 157.
    Cheung YW, Cradock JC, Vishnuvajjala, Flora KP. Stability of cisplatin, iproplatin, carboplatin, and tetraplatin in commonly used intravenous solutions. Am J Hosp Pharm 1987;44:124–30.PubMedGoogle Scholar
  158. 158.
    Chang Y, Sternson LA, Repta AJ. Development of a specific analytical method forcis-dichlorodiammineplatinum(II) in plasma. Anal Lett 1978;B11:449–59.Google Scholar
  159. 159.
    Riley CM, Sternson LA, Repta AJ. High-performance liquid chromatography ofcis-dichlorodiammineplatinum(II) using chemically-bonded and solvent-generated ion exchanges. J Chromatogr 1981;217:405–20.CrossRefGoogle Scholar
  160. 160.
    Riley CM, Sternson LA, Repta AJ. High-performance liquid chromatography of cisplatin. J Pharm Sci 1983;72:351–5.PubMedGoogle Scholar
  161. 161.
    Riley CM, Sternson LA, Repta AJ, Slyter SA. Reactivity ofcis-dichlorodiammineplatinum(II) (cisplatin) toward selected nucleophiles. Polyhedron 1982;1:201–2.CrossRefGoogle Scholar
  162. 162.
    Hincal AA, Long DF, Repta AJ. Cisplatin stability in aqueous parenteral vehicles. J Parenter Drug Assoc 1979;33:107–16.PubMedGoogle Scholar
  163. 163.
    Safirstein R, Daye M, Guttenplan JB. Mutagenic activity and identification of excreted platinum in human and rat urine and rat plasma after adminstration of cisplatin. Cancer Lett 1983;18:329–38.CrossRefPubMedGoogle Scholar
  164. 164.
    Le Roy AF, Wehling M, Gormley P, Egorin M, Ostrow S, Bachur N, et al. Quantitative changes incis-dichlorodiammineplatinum(II) speciation in excreted urine with time after iv infusion in man: methods of analysis, preliminary studies, and clinical results. Cancer Treat Rep 1980;64:123–32.PubMedGoogle Scholar
  165. 165.
    De Spiegeleer B, Siegers G, Van den Bossche W, De Moerloose P. Quantitative analysis ofcis-dichloro-diammineplatinum(II) by high performance thin layer chromatography. J Chromatogr 1984;315:481–7.CrossRefPubMedGoogle Scholar
  166. 166.
    Long DF, Repta AJ, Sternson AJ. The reactivity of cisplatin in plasma, implications for sample handling in pharmacokinetic studies. Int J Pharm 1980;6:167–73.CrossRefGoogle Scholar
  167. 167.
    Himmelstein KJ, Patton TF, Belt RJ, Taylor S, Repta AJ, Sternson LA. Clinical kinetics of intact cisplatin and some related species. Clin Pharmacol Ther 1981;29:658–64.PubMedGoogle Scholar
  168. 168.
    Patton TF, Repta AJ, Sternson LA, Belt RJ. Pharmacokinetics of intact cisplatin in plasma. Infusion versus bolus dosing. Int J Pharm 1982;10:77–85.CrossRefGoogle Scholar
  169. 169.
    Riley CM, Sternson LA, Repta AJ, Siegler RW. Highperformance liquid chromatography of platinum complexes on solvent generated anion exchangers. III. Application to the analysis of cisplatin in urine using automated column switching. J Chromatogr 1982;229:373–86.PubMedGoogle Scholar
  170. 170.
    Riley CM, Sternson LA, Repta AJ, Bannister SJ. Intact cisplatin in urine following intravenous infusion. J Pharm Pharmacol 1982;34:826.Google Scholar
  171. 171.
    Daley-Yates PT, McBrien DCH. Cisplatin metabolites in plasma, a study of their pharmacokinetics and importance in the nephrotoxic and antitumour activity of cisplatin. Biochem Pharmacol 1984;33:3063–70.CrossRefPubMedGoogle Scholar
  172. 172.
    Daley-Yates PT, McBrien DCH. A study of the protective effect of chloride salts on cisplatin nephrotoxicity. Biochem Pharmacol 1985;34:2363–9.CrossRefPubMedGoogle Scholar
  173. 173.
    Pendyala L, Cowens JW, Creaven PJ. Studies on the pharmacokinetics and metabolism ofcis-dichloro-trans-dihydroxy-bis-isopropylamine platinum(IV) in the dog. Cancer Treat Rep 1982;66:509–16.PubMedGoogle Scholar
  174. 174.
    Pendyala L, Greco W, Cowens JW, Madajewicz S, Creaven PJ. Pharmacokinetics ofcis-dichloro-trans-dihydroxy-bis-isopropylamine platinum IV (CHIP) in patients with advanced cancer. Cancer Chemother Pharmacol 1983;11:23–8.CrossRefPubMedGoogle Scholar
  175. 175.
    Pendyala L, Cowens JW, Chheda GB, Dutta SP, Creaven PJ. Identification ofcis-dichloro-bis-isopropylamine platinum(II) as a major metabolite of iproplatin in humans. Cancer Res 1988;48:3533–6.PubMedGoogle Scholar
  176. 176.
    Harland SJ, Newell DR, Siddik ZH, Chadwick R, Calvert HA, Harrap KR. Pharmacokinetics ofcis-diammine-1,1-cyclo-butane dicarboxylate platinum(II) in patients with normal and impaired renal function. Cancer Res 1984;44:1693–7.PubMedGoogle Scholar
  177. 177.
    Gaver RC, George AM, Duncan GF, Morris AD, Deeb G, Faulkner HC, et al. The disposition of carboplatin in the beagle dog. Cancer Chemother Pharmacol 1988;21:197–202.CrossRefPubMedGoogle Scholar
  178. 178.
    Parsons PJ, Morrison PF, Le Roy AF. Determination of platinum-containing drugs in human plasma by liquid chromatography with reductive electrochemical detection. J Chromatogr 1987;385:323–35.CrossRefPubMedGoogle Scholar
  179. 179.
    Baumann RA, Gooijer C, Velthorst NH, Frei RW, Klein I, Van der Vijgh WJF. Quantitative determination of cisplatin in body fluids by liquid chromatography with quenched phosphorescence detection. J Pharm Biomed Anal 1987;5:165–70.CrossRefGoogle Scholar
  180. 180.
    Malfoy B, Hartmann B, Macquet JP, Leng M. Immunochemical studies of DNA modified bycis-diamminedichloroplatinum(II)in vivo andin vitro. Cancer Res 1981;41:4127–31.PubMedGoogle Scholar
  181. 181.
    Parsons PJ, Le Roy AF. Determination ofcis-diamminedichloroplatinum(II) in human plasma using ion-pair chromatography with electrochemical detection. J Chromatogr 1986;378:395–408.PubMedGoogle Scholar
  182. 182.
    De Waal WAJ, Maessen FJMJ, Kraak JC. Analysis of platinum species originating fromcis-diamminedichloroplatinum(II) (cisplatin) in human and rat plasma by high-performance liquid chromatography with on-line inductively coupled plasma atomic emission spectrometric detection. J Chromatogr 1987;407:253–72.CrossRefPubMedGoogle Scholar
  183. 183.
    Fichtinger-Schepman AMJ, Baan RA, Luiten-Schuite A, Van Dijk M, Lohman PHM. Immunochemical quantification of adducts induced bycis-diamminedichloroplatinum and analysis of adduct-related DNA-unwinding. Chem Biol Interac 1985;55:275–88.CrossRefGoogle Scholar
  184. 184.
    Sundquist WI, Lippard SJ, Stollar BD. Monoclonal antibodies to DNA modified withcis- ortrans-diamminedichloroplatinum(II). Proc Natl Acad Sci USA 1987;84:8225–9.PubMedGoogle Scholar
  185. 185.
    Poirier MC, Lippard SJ, Zwelling LA, Ushay HM, Kerrigan D, Thill CC, et al. Antibodies elicited againstcis-diamminedichloroplatinum(II)-modified DNA are specific forcis-diamminedichloroplatinum(II)-DNA adducts formedin vivo andin vitro. Proc Natl Acad Sci USA 1982;79:6443–7.PubMedGoogle Scholar
  186. 186.
    Terheggen PMAB, Floot BGJ, Scherer E, Begg AC, Fichtinger-Schepman AMJ, Den Engelse L. Immunocytochemical detection of interaction products ofcis-diamminedichloroplatinum(II) andcis-diammme(1,1-cyclobutane-dicarboxylato)platinum(II) with DNA in rodent tissue sections. Cancer Res 1987;47:6719–26.PubMedGoogle Scholar
  187. 187.
    Frankfurt OS. Flow cytometry analysis of DNA damage and the evaluation of cytotoxicity of alkylating agents. Cancer Res 1987;47:5537–41.PubMedGoogle Scholar
  188. 188.
    Den Engelse L, Bax J, Terheggen PMAB, Van Schooten FJ, Van Benthem J, Wild CP, et al. Single cell analysis of DNA modifications induced by carcinogens and cytostatic drugs. Ann Ist Super Sanita 1989;25:11–20.PubMedGoogle Scholar

Copyright information

© Royal Dutch Association for Advancement of Pharmacy 1992

Authors and Affiliations

  • T. J. M. Hodes
    • 1
  • W. J. M. Underberg
    • 1
  • G. Los
    • 2
  • J. H. Beijnen
    • 3
  1. 1.Department of Pharmaceutical Analysis, Faculty of PharmacyState University of UtrechtTB Utrechtthe Netherlands
  2. 2.Department of Medicine, Division of Haematology/OncologyUniversity of California/San DiegoLa JollaUSA
  3. 3.Slotervaart Hospital/The Netherlands Cancer InstituteEC Amsterdamthe Netherlands

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