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N-oxides of phenothiazine antipsychotics: effects on in vivo and in vitro estimates of dopaminergic function.

Although it is known that N-oxidation is a major route for the metabolism of tertiary amine drugs in humans, the extent to which N-oxide (NO) metabolites of clinically used phenothiazine antipsychotics contribute to the neuropharmacology of the parent drug has been uncertain. After direct lateral ventricular injection of rats, both fluphenazine-NO and trifluoperazine-NO (piperazinyl-4-NO) had significant antidopaminergic activity as shown by their antagonism of amphetamine-induced locomotion and, to a lesser extent, of apomorphine-induced stereotypy. In vitro, fluphenazine-NO and trifluoperazine-NO inhibited both [3H]spiperone binding to rat striatal membranes and dopamine-stimulated adenylate cyclase activity in striatal homogenates. Conversely, chlorpromazine (CPZ)-NO (side-chain oxide) did not have significant antidopaminergic activity in either in vitro test, nor did it block amphetamine or apomorphine-induced behavior when centrally administered. These latter results were surprising because it had been reported that CPZ-NO had significant antidopaminergic activity when administered by i.p. injection. In our experiments, i.p. administration of CPZ-NO or CPZ resulted in increased concentrations in brain of the acidic metabolites of dopamine, 3,4-dihydroxyphenylacetic acid and homovanillic acid. However, for CPZ-NO, this was shown to occur concomitantly with the peripheral conversion of the NO back to the parent drug. This suggests that although CPZ-NO does not itself have antidopaminergic properties, it may be readily converted to CPZ or other active species that contribute to pharmacological responses. These data suggest that the NOs of the phenothiazines may contribute to the neuropharmacological actions of antipsychotic drugs via several mechanisms, and underscore the necessity of correlating metabolic and neuropharmacological data.