Timiperone

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.

Abstract: The disposition and metabolism of timiperone (TP), a new butyrophenone antipsychotic, were studied in the rat, dog, and monkey given [14C]TP orally at different dose levels. [14C]TP was absorbed by the three species; the elimination of radioactivity from the blood was most rapid in the rat, and slowest in the dog. In the rat, blood and tissue concentrations of radioactivity were dose-dependent, and persisted after low and high doses. Tissue/blood ratios of radioactivity concentration in most of the rat tissues were much larger than 1.0, indicating that TP has a high affinity for the tissues. Approximately 19, 36, and 54% of the administered dose were excreted into dog, rat, and monkey urine, respectively, within 3 days, and the residue into the feces. [14C]TP was metabolized by N-dealkylation and the reduction of the butyrophenone sidechain to form 4-[4-(2,3-dihydro-2-thioxo-1H-benzimidazol-1-yl)-1-piperidinyl]-1-(4-fluorpheny l)-1-butanol (M-II), 2,3-dihydro-1-(4-piperidinyl)-2-thioxo-1H-benzimidazole (M-V), and N-(4-fluorophenylacetyl)glycine (M-b-l). Urinary major metabolites in all the species were M-V and M-b-l. Metabolite patterns in the rat brain indicated that unchanged TP accounted for the major part of total radioactivity. Similar patterns were obtained in rat and dog plasma, but not in monkey plasma.

Abstract: Remitted schizophrenic outpatients were prophytact~~a~~y treated to prevent reIapse with three d@erent doses of timiperone or sulpiride for a year in a double-blind controlled study employing a randomized design, Each drug’s ability to prevent relapse was evaluated by counting the number of subjects with different outcomes (remission, relapse, adverse reactions) during the trial andlor the number of symptom-free days for each sties before any sign of relapse or adverse reactions speared, Patients were ra~omly assigned to the following drugs, which were ora& administered once every night: placebo; timiperone 1 mg, 3 mg, 6 mg; sulpiride 100 mg, 300 mg, 600 mg. Data from previous studies involving haloperidol and propericiazine were utilized as a retrospective placebo group to compare the characteristics of the four drugs for maintenance treatment of remitted schizophrenic outpatients. Both timiperone and suipiride increased the number of patients in remission and decreased the number of patients who relapsed, compared with the palcebo group. With timiperone, there was an especially marked increase in the number of patients who showed signs of adverse reactions compared with sulpiride. Sulpiride was the only drug that increased the number of dose-dependent symptom-free days. However, both of these drugs signiftcantly increased the number of symptom-free days compared with placebo. By comparing the dose-response curves offour drugs tested in the same fashion, ~~operidol and su~piride were superior to properi~i~ine and timiperone because they displayed a wider dose range for the maintenance treatment of remitted schizophrenic outpatients.