Received for publication April 16, 2007.
Revised June 4, 2007.
Accepted for publication June 5, 2007.

Inhibition of Human Thiopurine S-Methyltransferase (TPMT) by Various NSAIDs 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. Present study was carried out to investigate the inhibitory potential of 15 non-steroidal anti-inflammatory drugs (NSAIDs) on the 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 HPLC-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 (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 co-administration of thiopurines and various NSAIDs may lead to drug interactions.

Key words: anti-inflammatory drugs, drug-drug interactions, enzyme inhibitors, methyl transferase