Disposition and metabolism of timiperone in the rat, dog, and monkey.

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.