Abstract
Results: Incubation in vitro of human recombinant and erythrocyte (RBC) thiopurine methyl transferase (TPMT) with furosemide, bendroflumethiazide and trichlormethiazide demonstrated inhibition of both enzyme preparations, with IC50 values of 170 μM, 360 μM and 1 mM, respectively. Kinetic studies revealed that the inhibition was mixed or non-competitive with regard both to the thiopurine substrate 6-mercaptopurine (6-MP) and the methyl donor S-adenosyl-L-methionine.
Conclusion: Since S-methylation is a major pathway in the metabolism of thiopurines, our data point to the possibility of a clinically significant diuretic-thiopurine interaction in patients treated simultaneously with these drugs.
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Aarbakke J (1995) Biology and pharmacology of thiopurines. Ped Hemat Oncol. 12:511–519
paterson ARP, Tidd DM (1975) 6-Thiopurines. In Antineoplastic and immunosuppressive agentsII, Sartorelli AC, Johns DG. (eds.) Springer, New York 384–403
Remy CN (1963) Metabolism of thiopyrimidines and thiopurines: S-methylation with S-5′-adenosylmethionine transmethylase and catabolism in mammalian tissue. J Biol Chem 238: 1078–1084
Woodson LC, Weinshilboum RM (1983) Human kidney thiopurine methyltransferase: Purification and biochemical properties. Biochem Pharmacol 32: 819–826
Woodson LC, Dunnette JH, Weinshilboum RM (1982) Pharmacogenetics of human thiopurine methyltransferase: Kidney-erythrocyte correlation and immunotitration studies. J Pharmacol Exp Ther 222:174–181
Szumlanski CL, Honchel R, Scott MC, Weinshilboum RM (1992) Human liver thiopurine methyltransferase pharmacogenetics: biochemical properties, liver-erythrocyte correlation and presence of isoenzymes. Pharmacogenetics 2:148–159
Lennard L, Lilleyman JS, Van Loon J, Weinshilboum RM (1990). Genetic variation in response to 6-mercaptopurine for childhood acute lymphoblastic leukaemia. Lancet 336:225–229
Chocair PR, Duley JA, Simmonds HA, Cameron JS (1992) The importance of thiopurine methyltransferase activity for the use of azathioprine in transplant recipients. Transplantation 53:1051–1056
Weinshilboum RM, Sladek SL (1980) Mercaptopurine pharmacogenetics: monogenetic inheritance of erythrocyte methyltransferase activity. Am J Human Genet 32:651–662
Klemetsdal B, Tollefsen E, Loennechen T, Johnsen K, Utsi E, Gisholt K, Wist E, Aarbakke J (1992) Interethnic difference in thiopurine methyltransferase activity. Clin Pharmacol Ther 51:24–31
Klemetsdal B, Wist E, Aarbakke J (1993) Gender difference in red blood cell thiopurine methyltransferase activity. Scand J Clin Lab Invest 53:747–749
Klemetsdal B, Straume B, Lysaa R, Giverhaug T, Aarbakke J (1995) Erythrocyte fraction affects red blood cell thiopurine methyltransferase activity. Eur J Clin Pharmacol 48:495–499
Woodson LC, Ames MM, Selassie CD, Hansch C, Weinshilboum RM (1983) Thiopurine methyltransferase: aromatic thiol substrates and inhibition by benzoic acid derivatives. Mol Pharmacol 24:471–478
Deininger M, Szumlanski CL, Otterness DM, Van Loon J, Ferber W, Weinshilboum RM (1994) Purine substrates for human thiopurine methyltransferase. Biochem Pharmacol 48:2135–2138
Szumlanski CL, Weinshilboum RM (1995) Sulphasalazine inhibition of thiopurine methyltransferase: possible mechanism for interaction with 6-mercaptopurine and azathioprine. Br J Clin Pharmacol 39:456–459
Klemetsdal B, Straume B, Wist E, Aarbakke J (1993) Identification of factors regulating thiopurine methyltransferase activity in a Norwegian population. Eur J Clin Pharmacol 44:147–152
Weinshilboum RM, Raymond FA, Pazmino PA (1978) Human erythrocyte thiopurine methyltransferase: Radiochemical microassay and biochemical properties. Clin Chim Acta 85:323–333
Honchel R, Aksoy I, Szumlanski C, Wood TC, Otterness DM, Wieben ED, Weinshilboum RM (1993) Human thiopurine methyltransferase: molecular cloning and expression of T84 colon carcinoma cell cDNA. Mol Pharmacol 43:878–887
Segel IH (1975) Enzyme kinetics, John Wiley, New York
Van Meyel JJM, Gerlag PGG, Smits P, Russel FGM, Tan Y, Van Ginneken CAM, Gribnau FWJ (1992) Absorption of high dose furosemide (frusemide) in congestive heart failure. Clin Pharmacokinet 22:308–318
Ponto LLB, Schoenwald RD (1990) Furosemide (frusemide). A pharmacokinetic/pharmacodynamic review (part I). Clin Pharmacokinet 18:381–408
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Lysaa, R.A., Giverhaug, T., Libæk Wold, H. et al. Inhibition of human thiopurine methyltransferase by furosemide, bendroflumethiazide and trichlormethiazide. Eur J Clin Pharmacol 49, 393–396 (1996). https://doi.org/10.1007/BF00203784
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DOI: https://doi.org/10.1007/BF00203784