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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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