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Drug Metabolism and Disposition Fast Forward
First published on June 6, 2007; DOI: 10.1124/dmd.107.016287

0090-9556/07/3509-1452-1454$20.00
DMD 35:1452-1454, 2007

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SHORT COMMUNICATION

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

Kersti Oselin, and Kaili Anier

Department of Pharmacology, Tartu University, Tartu, Estonia

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 Ki value for each compound, we performed kinetic analysis at five different inhibitor concentrations close to the IC50 value obtained in preliminary experiments. Naproxen (Ki = 52 µM), mefenamic acid (Ki = 39 µM), and tolfenamic acid (Ki = 50 µM) inhibited TPMT activity in a noncompetitive manner. The estimated Ki values for the inhibition of TPMT by ketoprofen (Ki = 172 µM) and ibuprofen (Ki = 1043 µM) 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.

Address correspondence to: Dr. Kersti Oselin, Department of Pharmacology, Tartu University, Ravila 19, 51014 Tartu, Estonia. E-mail address: kersti.oselin{at}ut.ee






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