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After a single dose of the butyrophenone neuroleptic haloperidol, behavioral effects and detectable drug levels in rat brain can last for several weeks. To determine if such persistence is a general property of neuroleptics, we compared drug levels and effects after IP administration of two butyrophenones (haloperidol and bromperidol), a high potency (fluphenazine) and a low potency (chlorpromazine) phenothiazine. Drug levels in brain tissue were measured by high pressure liquid chromatography and behavioral effects monitored as inhibition of apomorphine-induced stereotypy. Estimated near terminal elimination half-lives (t 1/2) from brain for acutely administered chlorpromazine (20 mg/kg) and fluphenazine (1 mg/kg) were 0.41 and 0.62 days, respectively, and neither drug was detectable after 4 days. Fluphenazine given daily for 5 days showed an only slightly slower elimination (t 1/2 = 1.1 days). In contrast, near-terminal elimination half-lives from brain for haloperidol and bromperidol (both at 1 mg/kg, IP) were much longer (6.6 and 5.8 days, respectively), and each was detectable for 21 days after dosing. Inhibition of apomorphine-induced stereotypy correlated highly (r = 0.95) with brain levels of haloperidol. For fluphenazine, given once or repeatedly, early inhibition was replaced within 1 week by supersensitivity to apomorphine which persisted for up to 3 weeks. These findings, indicating marked differences in clearance and recovery times after dosing with butyrophenones and phenothiazines, have clear implications for studies of the effects of neuroleptic drugs in rats.(ABSTRACT TRUNCATED AT 250 WORDS)

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Plasma neuroleptic levels in 41 patients (21 men, 20 women, aged 18 to 74) on haloperidol therapy were examined in relation to their age by means of radioreceptor assay. There was no significant difference among three age groups (below 45 years, 46 to 60 years, over 60 years) in the ratio of the plasma neuroleptic level to daily dose (nM/mg/kg), but a significant difference in the plasma neuroleptic level was found between the average values in parkinsonian (19.1 +/- 8.5 nM, M +/- SD) and nonparkinsonian (5.5 +/- 3.0 nM, M +/- SD) patients. There was, however, no significant difference in the incidence of parkinsonian symptoms between the young (below 60 years) and the old (over 60 years) age groups. These results suggest that in contrast to the previously reported study with chlorpromazine, the plasma neuroleptic level of haloperidol is not altered with aging and that parkinsonian symptoms induced by haloperidol occur simply in a plasma-neuroleptic-level-dependent manner.