Inhibition of human thiopurine S-methyltransferase by various nonsteroidal anti-inflammatory drugs in vitro: a mechanism for possible drug interactions.
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.
Oselin
Kersti
K
Department of Pharmacology, Tartu University, Ravila 19, 51014 Tartu, Estonia. kersti.oselin@ut.ee
Anier
Kaili
K
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
D000636:Aminosalicylic Acids; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000493:Allopurinol; D008780:Methyltransferases; C022745:thiopurine methyltransferase; C032587:olsalazine