Inhibition of human thiopurine methyltransferase by furosemide, bendroflumethiazide and trichlormethiazide.
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 microM, 360 microM 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.


CONCLUSIONS
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.
Lysaa
R A
RA
Department of Pharmacology, University of Tromsø, Norway.
Giverhaug
T
T
Wold
H L
HL
Aarbakke
J
J
D001539:Bendroflumethiazide / Q000008:administration & dosage / Q000494:pharmacology*; D004232:Diuretics / Q000008:administration & dosage / Q000494:pharmacology*; D004912:Erythrocytes / Q000187:drug effects / Q000201:enzymology; D005665:Furosemide / Q000008:administration & dosage / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D007928:Lethal Dose 50; D015122:Mercaptopurine / Q000737:chemistry / Q000378:metabolism; D008745:Methylation; D008780:Methyltransferases / Q000037:antagonists & inhibitors*; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D012436:S-Adenosylmethionine / Q000737:chemistry / Q000378:metabolism; D014237:Trichlormethiazide / Q000008:administration & dosage / Q000494:pharmacology*
D004232:Diuretics; D011994:Recombinant Proteins; D001539:Bendroflumethiazide; D012436:S-Adenosylmethionine; D005665:Furosemide; D015122:Mercaptopurine; D008780:Methyltransferases; C022745:thiopurine methyltransferase; D014237:Trichlormethiazide