CYP2D6 and ABCB1 Genetic Variability: Influence on Paroxetine Plasma Level and Therapeutic Response

Gex‐Fabry, Marianne; Eap, Chin B.; Oneda, Beatrice; Gervasoni, Nicola; Aubry, Jean‐Michel; Bondolfi, Guido; Bertschy, Gilles

doi:10.1097/ftd.0b013e31817d6f5d

Cited by 122 publications

(82 citation statements)

References 55 publications

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“…Moreover, even if they might not be correlated with antidepressant intra-cerebral concentrations or clinical efficacy [22] , plasma antidepressant levels were not available in this study because of its naturalistic design. However, three recent studies failed to show a significant association between the C3435T polymorphism and antidepressant plasma level [23][24][25] in depressed patients.…”

Section: Discussionmentioning

confidence: 99%

Antidepressants and ABCB1 Gene C3435T Functional Polymorphism: A Naturalistic Study

Gressier

Verstuyft

et al. 2010

Neuropsychobiology

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Introduction: Pharmacogenetic factors may explain some of the interindividual variability of response to antidepressants in depressed patients. We focused on P-glycoprotein (P-GP), whose expression depends on a functional polymorphism of the ABCB1 gene (C3435T variants: dbSNP: rs1045642), the 3435CC genotype being linked to a high level of P-GP expression. Acting as an efflux pump at the blood-brain barrier, P-GP reduces the intracellular penetration of many drugs. Little is known about the interaction between P-GP and response to antidepressants. The objective of this study is to assess whether the response to antidepressants in depression differs in patients with the 3435CC genotype as compared to patients with the 3435CT and 3435TT genotypes. Methods: 117 in-patients with a major depressive episode requiring a new antidepressant treatment were enrolled in this prospective naturalistic 4-week study. Response to antidepressants was assessed using the Hamilton Depression Rating Scale, the Beck Depression Inventory, the Clinician Global Impression Improvement and Therapeutic Index, and weight change. ABCB1 genotyping was performed using the Taqman method. Clinical assessment was performed blind from genotypes. Results: We failed to show any significant effect of the ABCB1 polymorphism in position 3435 on antidepressant efficacy or tolerance. Discussion: While some in vitro studies showed an influence of P-GP on cerebral concentrations of antidepressants, our results do not support the hypothesis that the C3435T polymorphism is involved in therapeutic response and safety of antidepressants in naturalistic clinical conditions, confirming results of previous studies on efficacy. Nonetheless, some methodological limitations may explain our negative results.

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Section: Discussionmentioning

confidence: 99%

Antidepressants and ABCB1 Gene C3435T Functional Polymorphism: A Naturalistic Study

Gressier

Verstuyft

et al. 2010

Neuropsychobiology

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“…There is limited information available in relation to antidepressant transport by human P-gp per se. However, in common with escitalopram, pharmacogenetic studies have revealed an association between SNPs in ABCB1 and response to other antidepressants (Gex-Fabry et al, 2008;Kato et al, 2008;Nikisch et al, 2008;Uhr et al, 2008;Sarginson et al, 2010). These antidepressants, including citalopram and paroxetine, are thought to be P-gp substrates based on results from studies in P-gp knockout mice Uhr et al, , 2008Doran et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

P-glycoprotein Inhibition Increases the Brain Distribution and Antidepressant-Like Activity of Escitalopram in Rodents

O’Brien

O’Connor

Clarke

et al. 2013

Neuropsychopharmacol

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Despite the clinical prevalence of the antidepressant escitalopram, over 30% of escitalopram-treated patients fail to respond to treatment. Recent gene association studies have highlighted a potential link between the drug efflux transporter P-glycoprotein (P-gp) and response to escitalopram. The present studies investigated pharmacokinetic and pharmacodynamic interactions between P-gp and escitalopram. In vitro bidirectional transport studies revealed that escitalopram is a transported substrate of human P-gp. Microdialysisbased pharmacokinetic studies demonstrated that administration of the P-gp inhibitor cyclosporin A resulted in increased brain levels of escitalopram without altering plasma escitalopram levels in the rat, thereby showing that P-gp restricts escitalopram transport across the blood-brain barrier (BBB) in vivo. The tail suspension test (TST) was carried out to elucidate the pharmacodynamic impact of P-gp inhibition on escitalopram effect in a mouse model of antidepressant activity. Pre-treatment with the P-gp inhibitor verapamil enhanced the response to escitalopram in the TST. Taken together, these data indicate that P-gp may restrict the BBB transport of escitalopram in humans, potentially resulting in subtherapeutic brain concentrations in certain patients. Moreover, by verifying that increasing escitalopram delivery to the brain by P-gp inhibition results in enhanced antidepressant-like activity, we suggest that adjunctive treatment with a P-gp inhibitor may represent a beneficial approach to augment escitalopram therapy in depression.

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“…According to PharmGKB, 41 are missense SNPs and 124 polymorphic sites have allele frequency higher than 5% [3,8]. Polymorphic variations on ABCB1 (MDR1) gene influence on its expression [9,10], on their association with pharmacokinetics and bioavailability of drugs [11,12] and on their association with clinical effects [13,14]. Among 68 SNPs genotyped in various ethnical populations, 17 SNPs are in 5'-region, 19 in exonic regions (14 missense and 5 silent SNPs), 25 in intronic regions and 13 in the 3'-untranslated region (UTR) [3].…”

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confidence: 99%

Genotype Variability and Haplotype Profile of Abcb1 (Mdr1) Gene Polymorphisms in Macedonian Population

Naumovska

Nestorovska

Sterjev

et al. 2014

Prilozi

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The aim of this study was to evaluate the most common ABCB1 (MDR1, P-glycoprotein) polymorphisms in the population of R. Macedonia and compare the allele and haplotype frequencies with the global geographic data reported from different ethnic populations. The total of 107 healthy Macedonian individuals from the general population was included. Genotypes for the ABCB1 for three polymorphisms C1236T [rs1128503], G2677A/T [rs2032582] and C3435T [rs1045642] were analyzed by Real-Time PCR. Obtained allele frequencies for these three SNPs were similar to those observed in other European Caucasians. The detected genotype frequencies were 33.6% for 1236CC, 44.9% for 1236CT and 21.5% for 1236TT in exon 12; 32.7%, 44.9% and 22.4% for 2677GG, 2677GT and 2677GT consecutively in exon 21; and 25.2% for 3435CC, 52.3% for 3435CT and 22.5% for 3435TT in exon 26.Strong LD was observed in our study among all = 0.859, r 2 = 0.711). Eight different haplotypes were identified and the most prominent was the CGC haplotype (45.3%). Our study was the first to have documented the distribution of ABCB1 alleles, genotypes and haplotypes in the population of R. Macedonia. The obtained results can help in the prediction of different response to the drugs that are P-glycoprotein substrates. Additionally, in the era of individualized medicine the determination of the P-glycoprotein genotype might be a good predictive marker for determination of the subpopulations with higher risk to certain diseases.

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CYP2D6 and ABCB1 Genetic Variability: Influence on Paroxetine Plasma Level and Therapeutic Response

Cited by 122 publications

References 55 publications

Antidepressants and ABCB1 Gene C3435T Functional Polymorphism: A Naturalistic Study

Antidepressants and ABCB1 Gene C3435T Functional Polymorphism: A Naturalistic Study

P-glycoprotein Inhibition Increases the Brain Distribution and Antidepressant-Like Activity of Escitalopram in Rodents

Genotype Variability and Haplotype Profile of Abcb1 (Mdr1) Gene Polymorphisms in Macedonian Population

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