title: Carbonyl reduction of timiperone in human liver cytosol.
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.
authors.affiliation: Department of Psychiatry, Shiga University of Medical Science, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Shimoda
authors.forename: M
authors.initials: M
authors.lastname: Shibasaki
authors.forename: T
authors.initials: T
authors.lastname: Inaba
authors.forename: S W
authors.initials: SW
authors.lastname: Cheung
authors.forename: T
authors.initials: T
authors.lastname: Someya
authors.forename: S
authors.initials: S
authors.lastname: Takahashi
mesh_terms: D000429:Alcohol Oxidoreductases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014150:Antipsychotic Agents / Q000737:chemistry / Q000378:metabolism*; D002090:Butyrophenones / Q000737:chemistry / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004976:Ethacrynic Acid / Q000494:pharmacology; D000077604:Fomepizole; D006220:Haloperidol / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D010634:Phenobarbital / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D014812:Vitamin K / Q000494:pharmacology
chemical_list: D014150:Antipsychotic Agents; D002090:Butyrophenones; D004791:Enzyme Inhibitors; D011720:Pyrazoles; D014812:Vitamin K; C024159:timiperone; D000077604:Fomepizole; D000429:Alcohol Oxidoreductases; D006220:Haloperidol; D004976:Ethacrynic Acid; D010634:Phenobarbital