PT  - JOURNAL ARTICLE
AU  - Kersti Oselin
AU  - Kaili Anier
TI  - Inhibition of Human Thiopurine <em>S</em>-Methyltransferase by Various Nonsteroidal Anti-inflammatory Drugs in Vitro: A Mechanism for Possible Drug Interactions
AID  - 10.1124/dmd.107.016287
DP  - 2007 Sep 01
TA  - Drug Metabolism and Disposition
PG  - 1452--1454
VI  - 35
IP  - 9
4099  - http://dmd.aspetjournals.org/content/35/9/1452.short
4100  - http://dmd.aspetjournals.org/content/35/9/1452.full
SO  - Drug Metab Dispos2007 Sep 01; 35
AB  - 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. The American Society for Pharmacology and Experimental Therapeutics