References London, pp 307–308 and 317–318
ABPI (1990–1991) Association of the British Pharmaceutical Industry Data Sheet Compendium, Datapharm Publications,
Adamson PC, Balis FM, Steinberg SM, Poplack DG (1990b) Pharmacokinetics of mercaptopurine in children with acute lymphocytic leukaemia. New Engl J Med 323: 1565–1566
Adamson PC, Zimm S, Ragab AH, Steinberg SM, Balis F. Kamen BA, Vietti TJ, Gillespie A, Poplack DG (1990b) A phase II trial of continuous infusion 6-mercaptopurine for childhood solid tumours. Cancer Chemother Pharmacol 26: 343–344
Bach MA, Bach JF (1972) Activities of immunosuppressive agents in vitro. Clin Exp Immunol 11: 89–98
Balis FM, Holcenberg JS, Zimm S, Tubergen D, Collins JM, Murphy RF, Gilchrist GS, Hammond GS, Poplack DG (1987) The effect of methotrexate on the bioavailability of oral 6-mercaptopurine. Clin Pharmacol Ther 41: 384–387
Bennett LL, Allen PW (1971) Formation and significance of 6-methylthiopurine ribonucleotide as a metabolite of 6-mercaptopurine. Cancer Res 31:152–158
Bokkerink JPM, Bakker MAH, Hulscher TW, de Abreu RRA, Schrellen EDAM, van Laarhoven JPRM, de Bruyn CHMM (1986) Sequence-, time- and dose-dependent synergism of methotrexate in malignant humanT-lymphoblasts. Biochem Pharamcol 35: 3549–3555
British and Dutch Multiple Sclerosis Trial Group (1988) Double-masked trial of azathioprine in multiple slerosis. Lancet 11: 179–183
Brunschede H, Krooth RS (1973) Studies on the xanthine oxidase activity of mammalian cells. Biochem Genet 8: 341–350
Burchenal JH, Murphy ML, Ellison RR, Sykes MP, Tan TC, Leone LA, Karnofsky DA, Craver LF, Dargeon HW Rhoads CP (1953) Clinical evaluation of a new antimetabolite, 6-mercaptopurine, in the treatment of leukaemia and allied diseases. Blood 8: 965–999
Cadman EC, Heimer R, Davis L (1979) Enhanced 5-flurouracil nucleotide formation after methotrexate administration. Explanation of drug synergism. Science 205: 1135–1137
Calne RY, Alexandre GPJ, Murray JE (1962) A study of the effects of drugs in prolonging survival of homologous renal transplants in dogs. Ann NY Acad Sci 99: 743–761
Chalmers AH (1974) Studies on the mechanism of formation of 5-mercapto-1-methyl-4-nitroimidazole. A metabolite of the immunosuppressive drug azathioprine. Biochem Pharmacol 23: 1891–1901
Chan GLC, Erdmen GR, Gruber SA, Matas AJ, Canafax DM (1990) Azathioprine metabolism: pharmacokinetics of 6-mercaptopurine, 6-thiouric acid and 6-thioguanine nucleotides in renal transplant patients. J Clin Pharm 30: 358–363
Chessells JM (1982) Acute lymphoblastic leukaemia. Sem Hematol 19: 155–170
Christie NT, Drake S, Meyn RE, Nelson JA (1984) 6-Thioguanine induced DNA damage as a determinant of cytotoxicity in cultured Chinese hamster ovary cells. Cancer Res 44: 3665–3671
Cleland W W (1964) Dithiothreitol, a new protective reagent for SH groups. Biochemistry 3: 480–483
Cory JG (1986) Purine and pyrimidine nucleotide metabolism. In TM Devlin (ed) Textbook of biochemistry, 2nd edn, Wiles, New York, pp 489–529
Doerr IL, Wempen I, Clarke DA, Fox JJ (1961) Thiation of nucleosides III. Oxidation of 6-mercaptopurines. J Org Chem 26: 3401–3409
Elion GB (1969) The comparative metabolism of Imuran and 6-mercaptopurine in man. Proc Am Assoc Cancer Res 10: 21
Elion GB (1972) Significance of azathioprine metabolites. Proc R Soc Med 65: 257–260
Elion GB, Callahan SW, Hitchings GH, Rundles RW (1960) The metabolism of 2-amino-6-[(1-methyl-4-nitro-5-imidazoyl)thiolpurine (BW 57-323) in man. Cancer Chemother Rep 8: 47–52
Endresen L, Lie S, Stom-Methisen I, Rugstad HE, Stokke O (1990) Pharmacokinetics of oral 6-mercaptopurine: relationship between plasma levels and urine excretion of parent drug. Therap Drug Monit 12: 227–234
Erdmann GR, France LA, Bostrom BC, Canafax DM (1990) A reversed phase high performance liquid chromatography approach to determining total red blood cell concentrations of 6-thioguanine, 6-mercaptopurine, methylthioguanine and methylmercaptopurine in a patient receiving thiopurine therapy. Biomed Chromatog 4: 47–51
Fairchild CR, Maybaum J, Kennedy KA (1986) Concurrent unilateral chromatid damage and DNA strand breakage in response to 6-thioguanine treatment. Biochem Pharmacol 35: 3533–3541
Fournier C, Bach MA, Dardenne M, Bach IF (1973) Selective action of azathioprine on T cells. Transplant Proc 5: 523–526
Gale RP, Butturini A (1991) Maintenance chemotherapy and cure of childhood acute lymphoblastic leukaemia. Lancet 338: 1315–1318
Grant DM, Tang BK, Kalow W (1983) Variability in caffeine metabolism, Clin Pharmacol Ther 33: 591–602
Grant DM, Tang BK, Kalow W (1986) Effect of allopurinol on caffeine disposition in man. Br J Clin Pharmacol 21: 454–458
Guerciolini R, Szumlanski C, Weinshilboum RM (1991) Human liver xanthine oxidase: nature and extent of individual variation. Clin Pharmacol Ther 50: 663–672
Hale JP, Lilleyman JS (1991) Importance of 6-mercaptopurine dose in lymphobastic leukaemia. Arch Dis Child 66: 462–466
Hayder S, Lafolie P, Bjork O, Peterson C (1989) 6-mercaptopurine plasma levels in children with acute lymphoblastic leukaemia: relation to relapse risk and myelotoxicity. Ther Drug Monit 11: 617–622
Hemmens VJ, Moore DE (1984) Photo-oxidation of 6-mercaptopurine in aqueous solution. J Chem Soc Perkin Trans 11: 209–211
Hemmens VJ, Moore DE (1986) Photochemical sensitisation by azathioprine and metabolites: 1.6-mercaptopurine. Photochem Photobiol 43: 247–255
Higuchi T, Nakamura T, Wakisaka G (1976) Metabolism of 6-mercaptopurine in human leukaemia cells. Cancer Res 36: 3779–3783
Hill DL, Bennett LL (1969) Purification and properties of 5-phosphoribosylpyrophosphate amidotransferase from adenocarcinoma 755 cells. Biochemistry 8: 122–130
Holmes EW, Wyngaarden JB (1989) Hereditary xanthinurea. In: Scriver CR, Beaudet AL, Sly WS, Vale D (eds) The metabolic basis of inherited disease. McGraw-Hill, USA, pp 1085–1094
Kalow W Tang BK (1991) Use of caffeine metabolic ratios to explore CYPIA2 and xanthine oxidase activities. Clin Pharmacol Ther 50: 508–519
Kappos L, Stolle U, Rohrbach E, Haubitz I, Mertens HG (1988) The impact of long-term azathioprine on survival and incidence of malignances in multiple sclerosis. J Neurol 235: S94
Kappos L, Heun R, Mertens H-G (1990) A 10-year matched pairs study comparing azathioprine and no immunosuppression in multiple sclerosis. Eur Arch Psychiatry Clin Neurosci 240: 34–38
Kato Y, Matsushita T Yokoyama T, Mohri K (1991) Determination of 6-mercaptopurine in acute lymphoblastic leukaemia patients' plasma by high-performance liquid chromatography. Therap Drug Monitoring 13: 220–225
Kelly GE, Mahony JF, Sheil AGR, Meikle WD, Tiller DS, Horvath J (1987) Risk factors for skin carcinogenesis in immunosuppressed kidney transplant recipients. Clin Transplantation 1: 271–277
Kelly GE, Meikle WD, Moore DE (1989) Enhancement of UVinduced skin carcinogenesis by azathioprine: role of photochemical sensitisation. Photochem Photobiol 49: 59–65
Koren G, Ferrazini G, Sulh H, Langevin AM, Kapelushnik J, Klein J, Giesbrecht E, Soldin S, Greenberg M (1990) Systemic exposure to mercaptopurine as a prognostic factor in acute lymphocytic leukaemia in children. New Engl J Med 323: 17–21
Lafolie P, Hayder S, Bjork O, Peterson C (1991) Intraindividual variation in 6-mercaptopurine pharmacokinetics during oral maintenance therapy of children with acute lymphoblastic leukaemia. Eur J Clin Pharmacol 40: 599–601
Lavi L, Holcenberg JS (1985) A rapid and sensitive high performance liquid chromatographic assay for 6-mercaptopurine metabolites in red blood cells. Anal Biochem 144: 514–521
Lennard L (1985) Assay of 6-mercaptopurine in human plasma. J Chromatog 345: 441–446
Lennard L (1987) Assay of 6-thioinosinic acid and 6-thioguanine nuleotides, active metabolites of 6-mercaptopurine, in human red blood cells. J Chromatog 423: 169–178
Lennard L, Lilleyman JS (1987) Are children with lymphoblastic leukaemia given enough 6-mercaptopurine? Lancet II: 785–787
Lennard L, Lilleyman JS (1989) Variable 6-mercaptopurine metabolism and treatment outcome in childhood lymphoblastic leukaemia. J Clin Oncol 7: 1816–1823
Lennard L, Maddocks JL (1983) Assay of 6-thioguanine nucleotide, a major metabolite of azathioprine, 6-mercaptopurine and 6-thioguanine, in human red blood cells. J Pharm Pharmacol 35: 15–18
Lennard L, Brown CB, Fox M, Maddocks JL (1984) Azathioprine metabolism in kidney transplant recipients. Br J Clin Pharmacol 18: 693–700
Lennard L, Thomas S, Harrington CI, Maddocks JL (1985) Skin cancer in renal transplant recipients is associated with increased concentrations of 6-thioguanine nucleotide in red blood cells. Br J Dermatol 113: 723–729
Lennard L, Keen D, Lilleyman JS (1986) Oral 6-mercaptopurine in childhood leukaemia: parent drug pharmacokinetics and active metabolite concentrations. Clin Pharmacol Ther 40: 287–292
Lennard L, Harrington CI, Wood M, Maddocks JL (1987) Metabolism of azathioprine to 6-thioguanine nucleotides in patients with pemphigus vulgaris. Br J Clin Pharmacol 23: 227–233
Lennard L, Van Loon JA, Weinshilboum RM (1989) Pharmacogenetics of acute azathioprine toxicity: relationship to thiopurine methyltransferase genetic polymorphism. Clin Pharmacol Ther 46:149–154
Lennard L, Lilleyman JS, Van Loon JA, Weinshilboum RM (1990) Genetic variation in response to 6-mercaptopurine for childhood acute lymphoblastic leukaemia. Lancet 336: 225–229
Lennard L, Hale JP, Lilleyman JS (1991) 6-mercaptopurine metabolism and hypoxanthine phosphoribosyltransferase activity in childhood leukaemia. Br J Clin Pharmacol 32: 659P
Lewis AS, Murphy L, McCalla C, Fleary M, Purcell S (1984) Inhbition of mammalian xanthine oxidase by folate compounds and amethopterine. J Biol Chem 259:12–15
Lilleyman JS (1991) Variables and paradoxes in “maintenance” therapy of lymphoblastic leukaemia. Pediatr Hematol Oncol 8: ix-xii
Lin S-N, Jessup K, Floyd M, Wang T-P F, Van Buren CT, Caprioli RM, Kahan BD (1980) Quantitation of azathioprine and 6-mercaptopurine levels in renal transplant patients. Transplantation 29:290–294
Markowitz J, Rosa J, Grancher K, Aiges H, Daum F (1990) Long-term 6-mercaptopurine treatment in adolescents with Crohn's disease. Gastroenterol 99: 1347–1351
Murphy ML, Tan TC, Ellison RR, Karnofsky DA, Burchenal JH (1955) Clinical evaluation of chloropurine and thioguanine. Proc Am Assoc Cancer Res 2:36–39
Murray JE, Merrill JP, Harrison JH, Wilson RE, Dammin GJ (1963) Prolonged survival of human kidney homografts by immunosuppressive drug therapy. New Engl J Med 268: 1315–1323
Nyhan WL, Sweetman L, Carpenter DG, Carter CH, Hoefnagel D (1968) Effects of azathioprine in a disorder of uric acid metabolism and cerebral function. J Pediatrics 72:111–118
O'Brien JJ, Bayless TM, Bayless JA (1991) Use of azathioprine in the treatment of Crohn's Disease. Gastroenterology 101: 39–46
Odlind B, Hartvig P, Lundstrom B, Lonnerholm G, Tufveson G, Grefberg N (1986) Serum azathioprine and 6-mercaptopurine levels and immunosuppressive activity after azathioprine in uremic patients. Int J Immunopharmacol 8:1–11
Pai GS, Sprenkle JA, Do TT, Mareni CE, Migeon BR (1980) Localization of loci for hypoxanthine phosphoribosyltransferase and glucose-6-phosphate dehydrogenase from studies of human X-autosome translocation. Proc Natl Acad Sci USA 77: 2810–2813
Parker D, Bate CM, Craft AW Graham-Pole J, Malpas JS, Stansfield AG (1980) Liver damage in children with acute leukaemia and non-Hodgkin's lymphoma on oral maintenance chemotherapy. Cancer Chemother Pharmacol 4:121–127
Parks DA, Granger DN (1986) Xanthine oxidase: biochemistry, distribution and physiology. Acata Physiol Scand Suppl 548: 89–99
Pinkel D, Hernandez K, Borella L, Holton C, Aur R, Samoy G, Pratt C (1971) Drug dosage and remission duration in childhood lymphocytic leukaemia. Cancer 27: 247–256
Present DH (1988) Trends in medical therapy: metronidazole, azathioprine and 6-mercaptopurine in inflammatory bowel disease. Can J Gastroenterol 2 [Suppl A]: 57A-62A
Present DH, Korelitz BI, Wisch N, Glass JL, Sacher DB, Pasternack BS (1980) Treatment of Crohn's disease with 6-mercaptopurine. A long-term randomised double blind study. New Engl J Med 302: 981–987
Rhodes J, Bainton D, Beck P, Campbell H (1971) Controlled trial of azathioprine in Crohn's disease. Lancet 11:1273–1276
Riccuti F, Ruddle FH (1973) Assignment of nucleoside phosphorylase to D-14 and localization of X-linked loci in man by somatic cell genetics. Nature (London) 241: 180–182
Rosman M, Williams HE (1973) Leukocyte purine phosphoribosyl transfereses in human leukemia sensitive and resistant to 6-thiopurines. Cancer Res 33: 1202–1209
Rundles RW Elion GB (1984) Mercaptopurine “bioavailability”. New Engl J Med 310: 929
Saur H, Hantke U, Wilmanns (1988) Azathioprine lymphotoxicity. Potentially lethal damage by its imidazole derivatives. Arzneim-Forsch/Drug Res 38: 820–824
Schwartz RS, Stack J, Dameshek W (1958) Effect of 6-mercaptopurine on antibody production. Proc Soc Exp Biol Med 99: 164–167
Schmeigelow K, Bruunshuus I (1990) 6-Thioguanine nucleotide accumulation in red blood cells during maintenance chemotherapy for children with acute lymphblastic leukaemia, and its relation to leukopenia. Cancer Chemother Pharmacol 26: 288–292
Schmeigelow K, Pulczynska M (1990) Prognostic significance of hepatotoxicity during maintenance chemotherapy for childhood acute lymphoblastic leukaemia. Br J Cancer 61: 767–772
Schmeigelow K, Schroder H, Pulczynska MK, Heil M (1989) Maintenance chemotherapy for childhood acute lymphblastic leukaemia; relation of bone marrow- and hepato-toxicity to the concentration of methotrexate in erythrocytes. Cancer Chemothr Pharmacol 25: 65–69
Sulh H, Koren G, Whalen C, Soldin S, Zipursky A, Greenberg M (1986) Pharmacokinetic determinants of 6-mercaptopurine myelotoxicity and therapeutic failure in children with acute lymphoblastic leukaemia. Clin Pharmacol Ther 40: 604–609
Szumlanski CL, Scott MC, Weinshilboum RM (1988) Thiopurine methyltransferase pharmacogenetics: Human liver enzyme activity. Clin Pharmacol Ther 43: 134
Szawlowski PWS, Al-Safi SA, Dooley T, Maddocks JL (1985) Azathioprine suppresses the mixed lymphocyte reaction of patients with the Lesch-Nyhan syndrome. Br J Clin Pharmacol 20: 489–491
Tidd DM, Paterson ARP (1974a) Distinction between inhibition of nucleotide synthesis and the delayed cytotoxic reaction of 6-mercaptopurine. Cancer Res 34: 733–737
Tidd DM, Paterson ARP (1974b) A biochemical mechanism for the delayed cytotoxic reactions of 6-mercaptopurine. Cancer Res 34:738–746
Tjaden UR, De Bruijn EA (1990) Chromatographic analysis of anticancer drugs. J Chromatog 531: 235–294
Van Loon J, Weinshilboum RM (1982) Thiopurine methyltransferase biochemical genetics: human lymphocyte activity. Biochem Genet 20: 637–658
Voogd CE (1989) Azathioprine, a genotoxic agent to be considered non-genotoxic in man. Mutation Res 221: 133–152
Warnick CT, Paterson ARP (1973) Effect of methyl thicinosine on nucleotide concentrations in L5178Y cells. Cancer Res 33: 1711–1715
Weinshilboum R (1988) Pharmacogeneties of methylation: relationship to drug metabolism. Clin Biochem 21: 201–210
Weinshilboum R (1989) Thiol S-methyltransferase: I. Biochemistry. In: Damani LA (ed) Sulphur containing drugs and related organic compounds. Ellis Horwood, Chichester 2A, pp 121–142
Weinshilboum R (1989) Thiol S-methyltransferases: II. Pharmacogenetics. In: Damani LA (ed) Sulphur containing drugs and related organic compounds. Ellis Horwood, Chichester, UK 2A, pp 143–157
Weinshilboum RM, Sladek SL (1980) Mercaptopurine pharmacogenetics: Monogenic inheritance of erythrocyte thiopurine methyltransferase activity. Am J Hum Genet 32: 651–662
Weinshilboum RM, Raymond FA, Pazmino PA (1978) Human erythrocyte thiopurine methyltransferase: Radiochemical microassay and biochemical properties. Clin Chim Acta 85: 323–333
Willoughby JMT, Kumar PJ, Beckett J, Dawson AM (1971) Controlled trial of azathioprine in Crohn's disease. Lancet 2: 944–947
Wilson JM, Young AB, Kelley WN (1983) Hypoxanthineguanine phosphoribosyl transferase deficiency. The molecular basis of the clinical syndromes. N Eng J Med 309:900–910
Winkelstein A (1979) The effects of azathioprine and 6-mercaptopurine on immunity. J Immunopharmacol l: 429–454
Woodson LC, Maus TP, Reiter C, Weinshilboum RM (1981) Rat thiopurine methyltransferase: Regulation by testosterone. J Pharmacol Exp Ther 218: 734–738
Woodson LC, Dunnette JH, Weinshilboum RM (1982) Pharmacogenetics of human thiopurine methyltransferase: kidneyerythrocyte correlation and immunotitration studies. J Pharmacol Exp Ther 222: 174–184
Working Party on Leukaemia in Childhood (1986) Improvement in treatment for children with acute lymphoblastic leukaemia, the Medical Research Council UKALL Trials, 1972-84. Lancet 1: 408–411
Yamada M, Wasserman R, Lange B, Reichard BA, Wormer RB, Rovera G (1990) Minimal residual disease in childhood Blineage lymphoblastic leukaemia. New Eng J Med 323:448–455
Yeh GC, Phang JM (1983) Pyrroline-5-carboxylate stimulates the conversion of purine antimetabolites to their nucleotide forms by a redox-dependent mechanism. J Biol Chem 258: 9774–9779
Yudkin PL, Ellison GW, Ghezzi A, Goodkin DE, Hughes RAC, McPherson K, Merton J, Milanese C (1991) Overview of azathioprine treatment in multiple sclerosis. Lancet 338: 1051–1055
Zimm S, Collins JM, Riccardi R, O'Neill D, Narang PK, Chabner B, Poplack DG (1983a) Variable bioavailability of oral mercaptopurine. Is maintenance chemotherapy in acute lymphoblastic leukaemia being optimally delivered? New Engl J Med 308: 1005–1009
Zimm S, Collins JM, O'Niell D, Chabner BA, Poplack DG (1983a) Inhibition of first-pass metabolism in cancer chemotherapy. Interaction of 6-mercaptopurine and allopurinol. Clin Pharmacol Therap 34: 810–817
Zimm S, Ettinger LJ, Holcenberg JS, Kamen BA, Vietti TJ, Belasco J, Cogliano-Shutta N, Balis F, Lavi LE, Collins JM, Poplack DG (1985) Phase I and clinical pharmacological study of mercaptopurine administered as a prolonged intravenous infusion. Cancer Res 45: 1869–1873
Zimm S, Reaman G, Murphy RF, Poplack DG (1986a) Biochemical parameters of mercaptopurine activity in patients with acute lymphoblastic leukaemia. Cancer Res 46: 1495–1498
Zimm S, Johnson GE, Poplack DG (1986b) Modulation of thiopurine cytotoxicity in the HL-60 cell line by physiological concentrations of hypoxanthine. Cancer Res 46: 6286–6289
Zimm S, Strong JM (1987) A clinically useful ion pairing high performance liquid chromatographic assay for the monophosphate metabolites of thioguanine and mercaptopurine in neoplastic cells. Anal Biochem 160: 1–6
Zwelman B (1973) Immunosuppression by thiopurines. Transplant Proc 5: 1197–1201
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Lennard, L. The clinical pharmacology of 6-mercaptopurine. Eur J Clin Pharmacol 43, 329–339 (1992). https://doi.org/10.1007/BF02220605
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DOI: https://doi.org/10.1007/BF02220605