title: Inhibition of human thiopurine S-methyltransferase by various nonsteroidal anti-inflammatory drugs in vitro: a mechanism for possible drug interactions.
abstract: Thiopurine S-methyltransferase (TPMT) is a biotransformation phase II enzyme responsible for the metabolic inactivation of thiopurine drugs. The present study was carried out to investigate the inhibitory potential of 15 nonsteroidal anti-inflammatory drugs (NSAIDs) on human TPMT activity in vitro. TPMT activity was measured in pooled human erythrocytes in the absence and presence of various NSAIDs using the previously published high-performance liquid chromatography-UV method. To determine the inhibition type and K(i) value for each compound, we performed kinetic analysis at five different inhibitor concentrations close to the IC(50) value obtained in preliminary experiments. Naproxen (K(i) = 52 microM), mefenamic acid (K(i) = 39 microM), and tolfenamic acid (K(i) = 50 microM) inhibited TPMT activity in a noncompetitive manner. The estimated K(i) values for the inhibition of TPMT by ketoprofen (K(i) = 172 microM) and ibuprofen (K(i) = 1043 microM) indicated that the propionic acid derivatives were relatively weak inhibitors of TPMT. Our results suggest that coadministration of thiopurines and various NSAIDs may lead to drug interactions.
authors.affiliation: Department of Pharmacology, Tartu University, Ravila 19, 51014 Tartu, Estonia. kersti.oselin@ut.ee
authors.forename: Kersti
authors.initials: K
authors.lastname: Oselin
authors.forename: Kaili
authors.initials: K
authors.lastname: Anier
mesh_terms: D000493:Allopurinol / Q000378:metabolism; D000636:Aminosalicylic Acids / Q000378:metabolism; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D002851:Chromatography, High Pressure Liquid; D003627:Data Interpretation, Statistical; D004347:Drug Interactions; D004912:Erythrocytes / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D008780:Methyltransferases / Q000037:antagonists & inhibitors*; D013056:Spectrophotometry, Ultraviolet
chemical_list: D000636:Aminosalicylic Acids; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000493:Allopurinol; D008780:Methyltransferases; C022745:thiopurine methyltransferase; C032587:olsalazine