Drug distribution between blood and brain as a determinant of antipsychotic drug effects

Tsuneizumi, T.; Babb, Suzann M.; Cohen, Bruce M.

doi:10.1016/0006-3223(92)90085-e

Cited by 68 publications

(44 citation statements)

References 31 publications

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“…The concentrations necessary for the antagonistic potencies against 5-HT-evoked Na þ and Ca 2 þ fluxes are within the range of concentrations of antipsychotics reached in rat brain tissue after acute or chronic application, [45][46][47][48] and thus appear to be of therapeutical relevance. Furthermore, haloperidol concentrations in the range between 8.9 and 226 mM have been shown in human post-mortem brain tissue.…”

Section: Discussionmentioning

confidence: 80%

Antipsychotic drugs antagonize human serotonin type 3 receptor currents in a noncompetitive manner

et al. 2004

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The serotonin type 3 (5-HT 3 ) receptor is the only ligand-gated ion channel receptor for serotonin (5-HT). 5-HT 3 receptors play an important role in modulating the inhibitory action of dopamine in mesocorticolimbic brain regions. Neuroleptic drugs are commonly thought to exert their psychopharmacological action mainly through dopamine and serotonin type 2 (5-HT 2 ) receptors. Except for clozapine, a direct pharmacological interaction of neuroleptics with 5-HT 3 receptors has not yet been described. Using the concentration-clamp technique, we investigated the effects of flupentixol, various phenothiazines, haloperidol, clozapine and risperidone on Na þ -inward currents through 5-HT 3 receptors stably expressed in human embryonic kidney 293 cells, and through endogenous 5-HT 3 receptors of murine N1E-115 neuroblastoma cells. In addition, we studied their effects on Ca 2 þ influx, measured as a change in intracellular Ca 2 þ concentrations ([Ca 2 þ ] i ). All neuroleptic drugs, but not risperidone, antagonized Na þ -and Ca 2 þ -inward currents evoked by 5-HT (10 lM for 2 s and 1 lM, respectively) in a voltage-independent manner. Only clozapine was a competitive antagonist, while all other compounds turned out to be noncompetitive. Fluphenazine and haloperidol affected membrane anisotropy at concentrations below their IC 50 values, indicating that a change in membrane anisotropy might contribute to their antagonistic effect at the 5-HT 3 receptor. Only structure analogues of flupentixol and fluphenazine with a lipophilic side chain were potent antagonists against 5-HT-evoked Na þ and Ca 2 þ currents. Since 5-HT 3 receptors modulate mesolimbic and mesocortical dopaminergic activity, the functional antagonism of neuroleptics at 5-HT 3 receptors may contribute to their antipsychotic efficacy and may constitute a not yet recognized pharmacological principle of these drugs.

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Section: Discussionmentioning

confidence: 80%

Antipsychotic drugs antagonize human serotonin type 3 receptor currents in a noncompetitive manner

et al. 2004

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“…Another issue is that these lipophilic drugs are often concentrated in tissues such that adipocytes could be exposed to higher levels than those observed in serum. The tissue concentration of butyrophenone, for example, is 22-fold higher than plasma (Tsuneizumi et al, 1992), and trifluoperazine-sulfoxide accumulates to reach 450 times higher levels in tissues than in blood (Aravagiri et al, 1995). However, studies have shown that certain SGAs, such as olanzapine and risperidone, do not reach high concentrations in adipose tissue (Aravagiri et al, 1998) and the clearance seems to occur faster than with other tissues in rats (Aravagiri et al, 1998(Aravagiri et al, , 1999.…”

Section: Discussionmentioning

confidence: 99%

Atypical Antipsychotic Drugs Directly Impair Insulin Action in Adipocytes: Effects on Glucose Transport, Lipogenesis, and Antilipolysis

Vestri

Maianu

Moellering

et al. 2006

Neuropsychopharmacol

142

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Treatment with second-generation antipsychotics (SGAs) has been associated with weight gain and the development of diabetes mellitus, although the mechanisms are unknown. We tested the hypothesis that SGAs exert direct cellular effects on insulin action and substrate metabolism in adipocytes. We utilized two cultured cell models including 3T3-L1 adipocytes and primary cultured rat adipocytes, and tested for effects of SGAs risperidone (RISP), clozapine (CLZ), olanzapine (OLZ), and quetiapine (QUE), together with conventional antipsychotic drugs butyrophenone (BUTY), and trifluoperazine (TFP), over a wide concentration range from 1 to 500 mM. The effects of antipsychotic drugs on basal and insulin-stimulated rates of glucose transport were studied at 3 h, 15 h, and 3 days. Both CLZ and OLZ (but not RISP) at doses as low as 5 mM were able to significantly decrease the maximal insulin-stimulated glucose transport rate by B40% in 3T3-L1 cells, whereas CLZ and RISP reduced insulin-stimulated glucose transport rates in primary cultured rat adipocytes by B50-70%. Conventional drugs (BUTY and TFP) did not affect glucose transport rates. Regarding intracellular glucose metabolism, both SGAs (OLZ, QUE, RISP) and conventional drugs (BUTY and TFP) increased basal and/or insulin-stimulated glucose oxidation rates, whereas rates of lipogenesis were increased by CLZ, OLZ, QUE, and BUTY. Finally, rates of lipolysis in response to isoproterenol were reduced by the SGAs (CLZ, OLZ, QUE, RISP), but not by BUTY or TFP. These experiments demonstrate that antipsychotic drugs can differentially affect insulin action and metabolism through direct cellular effects in adipocytes. However, only SGAs were able to impair the insulin-responsive glucose transport system and to impair lipolysis in adipocytes. Thus, SGAs directly induce insulin resistance and alter lipogenesis and lipolysis in favor of progressive lipid accumulation and adipocyte enlargement. These effects of SGAs on adipocytes could explain, in part, the association of SGAs with weight gain and diabetes. Neuropsychopharmacology (2007) 32, 765-772.

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“…The observed differences in brain to plasma concentrations of remoxipride and its metabolites are consistent with the differences in distribution coefficients. Other types of DA antagonists have also markedly different ratios (Tsuneizumi et al, 1992). It has been reported that compounds with a low ratio, e.g., thioridazine have similar brain levels as compounds with a high ratio of brain to plasma concentrations, e.g., haloperidol.…”

Section: Discussionmentioning

confidence: 99%

Concentrations of remoxipride and its phenolic metabolites in rat brain and plasma. Relationship to extrapyramidal side effects and atypical antipsychotic profile

Ögren

Lundström

Nilsson

1993

J. Neural Transmission

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The cataleptic effect of remoxipride was examined in the horizontal bar test after i.v.,i.p. and s.c. administration to male rats. Remoxipride induced immediate catalepsy after high i.v. doses (ED50 = 49 mumol/kg) while peak effects were seen 60-90 min after i.p. administration (ED50 = 38 mumol/kg). Following s.c. administration remoxipride failed to produce a statistically significant catalepsy in the 20-100 mumol/kg dose range (ED50 > 100 mumol/kg). In contrast, haloperidol was found to be more effective in inducing catalepsy after i.v. (ED50 = 0.4 mumol/kg) than after i.p. or s.c. administration (ED50 = 0.9 mumol/kg). The atypical antipsychotic profile of remoxipride was more pronounced when the compound was given i.v. or s.c. as compared with the i.p. route. Plasma and brain (striatum and nucleus accumbens) concentrations of remoxipride and its active phenolic metabolites FLA 797(-) and FLA 908(-) were measured by high performance liquid chromatography. The 40 mumol/kg dose of remoxipride resulted in plasma and brain concentrations of remoxipride which were 300-1000-fold higher (depending on the route of administration) than the most potent of the phenolic metabolites, e.g., FLA 797(-). The plasma and brain concentrations of remoxipride and its phenolic metabolites were related to DA D2 receptor blocking potency and to the temporal course and effectiveness to induce catalepsy. This analysis suggested that the unbound concentrations of the phenolic metabolites were too low to play a major role in the DA blocking action of remoxipride. However, FLA 797(-) may contribute marginally to the cataleptic effects following high (i.p.) doses of remoxipride.

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Drug distribution between blood and brain as a determinant of antipsychotic drug effects

Cited by 68 publications

References 31 publications

Antipsychotic drugs antagonize human serotonin type 3 receptor currents in a noncompetitive manner

Antipsychotic drugs antagonize human serotonin type 3 receptor currents in a noncompetitive manner

Atypical Antipsychotic Drugs Directly Impair Insulin Action in Adipocytes: Effects on Glucose Transport, Lipogenesis, and Antilipolysis

Concentrations of remoxipride and its phenolic metabolites in rat brain and plasma. Relationship to extrapyramidal side effects and atypical antipsychotic profile

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