Open AccessCarbonyl Reduction of Timiperone in Human Liver Cytosol
Author(s) -
Shimoda Kazutaka,
Shibasaki Morikazu,
Lnaba Tadanobu,
Cheung Siu Wah,
Someya Toshiyuki,
Takahashi Saburo
Publication year - 1998
Publication title -
pharmacology & toxicology
Language(s) - English
Resource type - Journals
eISSN - 1600-0773
pISSN - 0901-9928
DOI - 10.1111/j.1600-0773.1998.tb01463.x
Subject(s) - haloperidol , reductase , chemistry , butyrophenone , alcohol dehydrogenase , cytosol , enzyme inhibitor , ic50 , menadione , endocrinology , pharmacology , enzyme , medicine , biochemistry , in vitro , biology , dopamine
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 IC 50 5–18 μM; ethacrynic acid IC 50 26–51 μM) 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 μM, two‐tailed t‐test, P<0.05). The Michaelis‐Menten constant (Km) 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 μM, 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 times higher than for haloperidol, indicating that metabolic clearance of timiperone by carbonyl reductase may be similar to or slightly higher than for haloperidol.