Carbonyl reduction of timiperone in human liver cytosol

This in vitro study using human liver enzymes was undertaken in order to compare the mechanism of metabolic reduction of timiperone, a potent butyrophenone neuroleptic, with that of haloperidol. Conversion of timiperone to reduced timiperone in liver cytosol was confirmed. The carbonyl reductase inhibitors (menadione IC50 5-18 mu M; ethacrynic acid IC50 26-51 mu M) potently inhibited both timiperone reductase and haloperidol reductase activity while 4-methyl-pyrazole (alcohol dehydrogenase inhibitor) had no effect and phenobarbital (aldehyde reductase inhibitor) had a weak inhibitory effect. The formation of reduced timiperone was highly correlated with the formation of reduced haloperidol (r= 0.87, n=6, P<0.02). Timiperone reductase activity was approximately 40% lower than haloperidol reductase activity (at a substrate concentration of 100 mu M, two-tailed t-test, P<0.05). The Michaelis-Menten constant (Rm) and maximum velocity (Vmax of reduced timiperone formation were much lower than reduced haloperidol formation (K-m values: 29.7+/-15.1 versus 381.3+/-1.1 mu M, n=3, P<0.01; V-max: 0.81+/-0.19 versus 6.00+/-1.47 nmol/mg/min; n=3, P<0.05). However, the ratio V-max/K-m (clearance) for timiperone was 1.3-2.4 rimes higher than for haloperidol, indicating that metabolic clearance of timiperone by carbonyl reductase may be similar to or slightly higher than for haloperidol.