Inhibition of haloperidol reduction by non-steroidal anti-inflammatory drugs in human liver cytosol.

A thorough knowledge of drug-drug interactions is crucial as the practice of multiple drug therapy escalates. In vitro studies using human liver enzymes are a valuable and non-invasive tool for predicting potential drug interactions in vivo. 1. A simple radio-TLC method was developed to monitor the formation of reduced haloperidol from haloperidol in human liver cytosol. 2. Indomethacin, known to be a potent inhibitor of 3a-hydroxysteroid dehydrogenase, was chosen as a reference for the evaluation of several arylpropionic acid derived non-steroidal anti-inflammatory drugs, ketoprofen, tiaprofenic acid, fenbufen, Ibuprofen, d-naproxen and 1-naproxen. The IC₅₀ ranged from 0.4-6.0 mM with indomethacin the most potent inhibitor of haloperidol carbonyl reductase. 3. The carbonyl reduction of haloperidol was inhibited significantly by these most commonly used non-steroidal anti-inflammatory drugs and the degree of inhibition reflected their pharmacological potency. 4. Sephadex G-100 fractionation of human liver cytosol yielded a fraction with haloperidol reductase activity at a molecular weight of about 32,000.