Inhibition of human thiopurine methyltransferase by furosemide, bendroflumethiazide and trichlormethiazide

Abstract

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.

Inhibition of Human Thiopurine S-Methyltransferase by Various Nonsteroidal Anti-inflammatory Drugs in Vitro: A Mechanism for Possible Drug Interactions

“…A 10-fold difference in IC 50 values has been reported for sulfasalazine, depending on whether the recombinant enzyme [IC 50 ϭ 70 -78 M (Szumlanski and Weinshilboum, 1995;Lewis et al, 1997)] or RBC [IC 50 ϭ 640 M (Shipkova et al, 2004)] were used as a source of enzyme. Similar findings have been reported for diuretics (Lysaa et al, 1996;Xin et al, 2005). The magnitude of inhibition observed in in vitro experiments may depend on the source of enzyme and on experimental conditions.…”

“…In several clinical trials, increased 6-TG nucleotide levels have been found in patients with inflammatory bowel disease treated with thiopurines and aminosalicylates compared with thiopurine monotherapy (Lowry et al, 2001;Dewit et al, 2002). In vitro studies using a recombinant human enzyme confirmed that olsalazine, 5-aminosalicylic acid, and sulfasalazine are noncompetitive inhibitors of TPMT (Szumlanski and Weinshilboum, 1995;Lewis et al, 1997).In addition to benzoic acid derivatives, clinically significant interactions via TPMT inhibition by furosemide, bendroflumethiazide, and trichlormethiazide may occur when administered simultaneously with thiopurines (Lysaa et al, 1996). Drugs such as prednisone, prednisolone, 6-methylprednisolone, cyclophosphamide, methotrexate, and trimethoprim-sulfamethoxazole, often used simultaneously with thiopurines in leukemic patients, had no effect on TPMT activity in vitro using lysates of red blood cells (RBC) (Jacqz-Aigrain et al, 1994).…”

“…In addition to benzoic acid derivatives, clinically significant interactions via TPMT inhibition by furosemide, bendroflumethiazide, and trichlormethiazide may occur when administered simultaneously with thiopurines (Lysaa et al, 1996). Drugs such as prednisone, prednisolone, 6-methylprednisolone, cyclophosphamide, methotrexate, and trimethoprim-sulfamethoxazole, often used simultaneously with thiopurines in leukemic patients, had no effect on TPMT activity in vitro using lysates of red blood cells (RBC) (Jacqz-Aigrain et al, 1994).…”

Thiopurine S-methyltransferase - characterization of variants and ligand binding

“…TPMT has been shown to bind a large number of heterocyclic compounds with polar substituents (albeit with varying affinity), and the corresponding thiols often act as substrates. Several clinically relevant substances inhibit the enzyme, and have been shown to affect treatment when administered concomitantly with thiopurines [37,38,39,40]. Substances capable of acting as substrates or inhibitors of the enzyme are summarized in Tables 1.3 To enable comparison with our own work, the results of the literature study presented herein has been limited to publications where (1) the relevant components of the biochemical system under study has been measured in (relative) isolation, and (2) the TPMT concentration has been estimated or determined using an established method.…”

Therapeutic drug monitoring of cytotoxic drugs

“…A possible drug±drug interaction was reported in a patient with refractory Crohn's disease who developed bone marrow suppression whilst receiving daily MP and olsalazine (two molecules of 5-aminosalicylic acid) [65]. Concurrent furosemide therapy could in¯uence the S-methylation of thiopurines as furosemide inhibits TPMT with an IC 50 of 170 mM [66], a concentration within the therapeutic range for frusemide. In addition, TPMT could interfere with disul®ram treatment in alcoholism [67].…”