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Evaluation of antipsychotic drugs as inhibitors of multidrug resistance transporter P-glycoprotein

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Abstract

Rationale

The multidrug resistance transporter, P-glycoprotein (P-gp), is involved in efflux transport of several antipsychotics in the blood–brain barrier (BBB).

Objectives

In the present study, we evaluated the inhibitory effect of the antipsychotics, i.e., risperidone, olanzapine, quetiapine, clozapine, haloperidol, chlorpromazine, a major metabolite of risperidone, 9-OH-risperidone, and a positive control inhibitor, PSC833, on the cellular uptake of a prototypic substrate of P-gp, rhodamine (Rhd) 123, in LLC-PK1 and L-MDR1 cells.

Materials and methods

After incubation of the antipsychotics (1–100 μM) and the positive (10 μM PSC833) or negative (1% dimethyl sulfoxide) controls with 5 μM Rhd 123 for 1 h, the effects of the antipsychotics on the intracellular accumulation of Rhd 123 were examined using a flow cytometric method.

Results

All the antipsychotics showed various degrees of inhibitory effects on P-gp activity. The rank order of the concentration of inhibitor to cause 50% of the maximal increment of intracellular Rhd 123 fluorescence (EC50) was: PSC833 (0.5 μM) < olanzapine (3.9 μM) < chlorpromazine (5.8 μM) < risperidone (6.6 μM) < haloperidol (9.1 μM) < quetiapine (9.8 μM) < 9-OH-risperidone (12.5 μM) < clozapine (30 μM). Considering that the antipsychotics’ plasma concentrations are generally lower than 1 μM, the present results suggest that olanzapine and risperidone are the only agents that may inhibit P-gp activity in the BBB. However, most of the antipsychotics are extensively accumulated in tissues. In addition, when given orally, the drug concentrations in the gastrointestinal tract are likely to be high.

Conclusions

Pharmacokinetic interactions due to inhibition of P-gp activity by the antipsychotics appear possible and warrant further investigation.

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Abbreviations

AAPs:

atypical antipsychotics

BBB:

blood–brain barrier

CNS:

central nervous system

EC50 :

the concentration of inhibitor to cause 50% of the maximal increment of intracellular fluorescence

ΔF:

median fluorescence

I:

the percentage of inhibition of P-gp activity

P-gp:

P-glycoprotein

DMEM:

Dulbecco’s modified eagle medium

Rhd 123:

Rhodamine 123

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Acknowledgement

This work was supported by NIH grant MH071811-01A1. None of the authors has conflicting interests that interfere with the integrity of the content of the article.

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Correspondence to Jun-Sheng Wang.

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Wang, JS., Zhu, HJ., Markowitz, J.S. et al. Evaluation of antipsychotic drugs as inhibitors of multidrug resistance transporter P-glycoprotein. Psychopharmacology 187, 415–423 (2006). https://doi.org/10.1007/s00213-006-0437-9

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  • DOI: https://doi.org/10.1007/s00213-006-0437-9

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