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| 1 | | Neuropharmacology 2005 Oct 49: 610-7 |
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| PMID | 15961125 |
| Title | Evaluation of the role of P-glycoprotein in the uptake of paroxetine, clozapine, phenytoin and carbamazapine by bovine retinal endothelial cells. |
| Abstract | Expression of the drug transport proteins, including P-glycoprotein (Pgp), in the brain vascular endothelium represents a challenge for the effective delivery of drugs for the treatment of several central nervous system (CNS) disorders including depression, schizophrenia and epilepsy. It has been hypothesized that Pgp plays a major role in drug efflux at the blood-brain barrier, and may be an underlying factor in the variable responses of patients to CNS drugs. However, the role of Pgp in the transport of many CNS drugs has not been directly demonstrated. To explore the role of Pgp in drug transport across an endothelial cell barrier derived from the central nervous system, the expression and activity of Pgp in bovine retinal endothelial cells (BRECs) and the effects of representative CNS drugs on Pgp activity were examined. Significant Pgp expression in BRECs was demonstrated by western analyses, and expression was increased by treatment of the cells with hydrocortisone. Intracellular accumulation of the well-characterized Pgp-substrate Taxol was markedly increased by the non-selective transporter inhibitor verapamil and the Pgp-selective antagonist PGP-4008, demonstrating that Pgp is active in these endothelial cells. In contrast, neither verapamil nor PGP-4008 affected the intracellular accumulation of [3H]paroxetine, [14C]phenytoin, [3H]clozapine or [14C]carbamazapine, indicating that these drugs are not substrates for Pgp. Paroxetine, clozapine and phenytoin were shown to be Pgp inhibitors, while carbamazapine did not inhibit Pgp at any concentration tested. These results indicate that Pgp is not likely to modulate patient responses to these drugs. |
| SCZ Keywords | schizophrenia |
| 2 | | Ther Drug Monit 2006 Oct 28: 668-72 |
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| PMID | 17038883 |
| Title | The relationship between P-glycoprotein (PGP) polymorphisms and response to olanzapine treatment in schizophrenia. |
| Abstract | P-glycoprotein (PGP) is a polymorphic efflux transporter located on the blood brain barrier that potentially affects the penetration of atypical antipsychotics into the central nervous system. Increased antipsychotic penetration to the primary site of activity may result in greater symptom improvement or the occurrence of side effects. This investigation examined the relationship between three common PGP polymorphisms (C1236T, G2677TA, and C3435T) and response to 6 weeks of open-label olanzapine treatment in patients with schizophrenia. Individuals with a PGP T allele at any of these polymorphisms would be expected to have greater antipsychotic penetration through the blood brain barrier, due to lower PGP activity. Forty-one patients were included in this reanalysis. For subjects in the 3435T allele carrier group, the plasma olanzapine level alone was positively associated with percent change in Brief Psychiatric Rating Scale score (p = 0.02). This relationship was not seen for the 3435CC group (p = 0.583). A similar trend was observed for negative symptom reduction, olanzapine plasma concentration, and the 3435T allele (p = 0.06), but this relationship did not meet statistical significance. There was no relationship between the PGP genotypes and changes in weight over the course of this 6 week study. The analysis using C1236T or G2677AT genotypes gave similar results, due to linkage of these polymorphisms.PGP polymorphisms may affect the penetration of olanzapine into the central nervous system as seen by a relationship between the 3435T allele, olanzapine plasma levels, and reduction in the positive symptoms of schizophrenia. This may stem from greater olanzapine central nervous system latency due to the presence of the 3435T allele and reduced PGP activity. The PGP C3435T genotype may help to determine positive symptom reduction from olanzapine clinically, but these findings should be replicated in a larger sample of subjects. |
| SCZ Keywords | schizophrenia |
| 3 | | Eur. J. Clin. Pharmacol. 2008 Jul 64: 697-703 |
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| PMID | 18478216 |
| Title | Effect of the novel antipsychotic drug perospirone on P-glycoprotein function and expression in Caco-2 cells. |
| Abstract | Perospirone (PER) is a novel atypical antipsychotic drug for the treatment of schizophrenia and other psychotic disorders. The multidrug resistance transporter, P-glycoprotein (Pgp), is involved in the efflux transport of several antipsychotics across the blood-brain barrier (BBB). The aim of the present study was to evaluate the modulating effect of PER on both Pgp activity and expression in Caco-2 cell monolayers.
The effects of PER were analyzed by means of rhodamine 123 (Rhd 123) assays, and those of Pgp expression were analyzed by flow cytometry and reverse transcriptase-PCR.
Perospirone at concentrations of 0.01-30 microM, which were found to be non-cytotoxic towards the Caco-2 cells, was observed to inhibit Pgp-mediated efflux transport of Rhd 123 in the cells as well as to down-regulate the cellular Pgp protein and MDR1 mRNA levels in a concentration-dependent manner. In the rhodamine accumulation assays, 30 microM PER produced a 429% increase of the cellular Rhd 123 concentration, which exceeded the inhibitory effect of the well-known Pgp inhibitor verapamil.
Our findings provide experimental evidence that PER is an inhibitor of Pgp which interferes directly and indirectly with the function of Pgp. |
| SCZ Keywords | schizophrenia |
