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

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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 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.

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