Clinical implications of thiopurine methyltransferase--optimization of drug dosage and potential drug interactions.
Thiopurine methyltransferase (TPMT) is a cytoplasmic enzyme that preferentially catalyzes the S-methylation of aromatic and heterocyclic sulphydryl compounds, such as the thiopurine drugs azathioprine, mercaptopurine, and thioguanine. These drugs form the same terminal metabolites, the thioguanine nucleotides (TGNs). One major influence on thiopurine therapy is the inherited activity of TPMT. TPMT "deficiency" is associated with grossly elevated TGN concentrations and profound toxicity after a short course of thiopurine therapy. Variant alleles producing a functional loss of TPMT activity have now been described. Although all the ethnic groups investigated to date have the same wild-type enzyme, TPMT variant allele frequencies vary. Potentially, TPMT activity can influence a number of compounds that could be coadministered with thiopurine drugs. After a therapeutic dose of aspirin, plasma concentrations of salicylic acid are within the range for TPMT inhibition. Sulfasalazine and its metabolite 5-aminosalicylic acid inhibit TPMT, and concurrent furosemide therapy could influence the S-methylation of thiopurines. In addition, TPMT could interfere with disulfiram treatment in alcoholism. TPMT S-methylates the diethyldithiocarbamate metabolite involved in disulfiram activation.
Lennard
L
L
Department of Medicine and Pharmacology, Royal Hallamshire Hospital, Sheffield, United Kingdom.
D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage* / Q000494:pharmacology*; D001379:Azathioprine / Q000008:administration & dosage / Q000494:pharmacology; D004347:Drug Interactions; D006801:Humans; D015122:Mercaptopurine / Q000008:administration & dosage / Q000494:pharmacology; D008780:Methyltransferases / Q000378:metabolism*; D011687:Purines / Q000008:administration & dosage* / Q000494:pharmacology*; D013866:Thioguanine / Q000008:administration & dosage / Q000494:pharmacology
D000964:Antimetabolites, Antineoplastic; D011687:Purines; D015122:Mercaptopurine; D008780:Methyltransferases; C022745:thiopurine methyltransferase; D013866:Thioguanine; D001379:Azathioprine