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Carbonyl reduction of timiperone in human liver cytosol.
- Source :
-
Pharmacology & toxicology [Pharmacol Toxicol] 1998 Oct; Vol. 83 (4), pp. 164-8. - Publication Year :
- 1998
-
Abstract
- 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 microM; ethacrynic acid IC50 26-51 microM) potently inhibited both timiperone reductase and haloperidol reductase activity, while 4-methylpyrazole (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 microM, 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 microM, n = 3, P < 0.01; Vmax: 0.81 +/- 0.19 versus 6.00 +/- 1.47 nmol/mg/min; n = 3, P < 0.05). However, the ratio Vmax/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.
- Subjects :
- Alcohol Oxidoreductases antagonists & inhibitors
Antipsychotic Agents chemistry
Butyrophenones chemistry
Chromatography, High Pressure Liquid
Cytosol drug effects
Enzyme Inhibitors pharmacology
Ethacrynic Acid pharmacology
Fomepizole
Haloperidol chemistry
Humans
In Vitro Techniques
Liver drug effects
Phenobarbital pharmacology
Pyrazoles pharmacology
Vitamin K pharmacology
Alcohol Oxidoreductases metabolism
Antipsychotic Agents metabolism
Butyrophenones metabolism
Cytosol metabolism
Haloperidol metabolism
Liver metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 0901-9928
- Volume :
- 83
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Pharmacology & toxicology
- Publication Type :
- Academic Journal
- Accession number :
- 9820877
- Full Text :
- https://doi.org/10.1111/j.1600-0773.1998.tb01463.x