Effect of CYP2D6, CYP2C9 and ABCB1 genotypes on fluoxetine plasma concentrations and clinical improvement in children and adolescent patients

Abstract

There is little known about pharmacogenetic of fluoxetine in children and adolescents. In this study, we evaluate, for the first time, the influence of CYP2D6, CYP2C9 and ABCB1 genotypes on the steady-state plasma concentrations of fluoxetine and its active metabolite (S)-norfluoxetine, and on the clinical improvement in children and adolescent patients receiving fluoxetine treatment. The assessment was performed in 83 patients after 8 and 12 weeks of treatment. Fluoxetine/(S)-norfluoxetine ratio was negatively correlated with the number of active CYP2D6 alleles (r: -0.450; P<0.001). Regarding the G2677T ABCB1 polymorphism, T allele carriers showed significantly higher improvements on the majority of scales including the Clinical Global Impression-Improvement scale (P<0.001). Our results confirm the influence of CYP2D6 genetic variants in fluoxetine pharmacokinetics and provide evidence for the potential effect of the ABCB1 genotype on the clinical improvement in children and adolescent patients treated with fluoxetine.

One-Year Follow-up of Children and Adolescents with Major Depressive Disorder: Relationship between Clinical Variables and Abcb1 Gene Polymorphisms

“…Interestingly, a previous study by Noordam found that the association between genetic variations in ABCB1 and risk of switching and discontinuation of antidepressant therapy was not limited to antidepressants that are P-gp substrates [32]. As noted above, a study by our group [23] found a significant association between the G2677T polymorphism of ABCB1 and clinical improvement after FLX treatment. Therefore, our results seem to support the role of P-gp in the bioavailability of FLX in the human brain, and it is possible that some drugs currently included in the non-P-gp substrate group may be misclassified [32].…”

“…The present study is a follow-up of patients recruited in 2011-2013 in the Child and Adolescent Psychiatry and Psychology Service of the Institute of Neurosciences at the Hospital Clinic in Barcelona and who had participated in previous investigations [23,35]. A total of 83 children aged between 10 and 17 years and who met DSM-IV-TR diagnostic criteria for MDD, obsessive compulsive disorder (OCD), or generalized anxiety disorder (GAD) were recruited.…”

“…However, MDD follow-up studies in adolescent samples are scarce. ment was found to be related to the ABCB1 gene [23]. This gene encodes the P-glycoprotein (P-gp), a plasma membrane transporter that has a critical role in the regulation of the blood-brain barrier transportation of many drugs, including antidepressants [24].…”

Possibility of Predicting Serotonin Transporter Occupancy From the In Vitro Inhibition Constant for Serotonin Transporter, the Clinically Relevant Plasma Concentration of Unbound Drugs, and Their Profiles for Substrates of Transporters

“…The relationship of the C3435T polymorphism to the antidepressant effect of SSRIs or SNRIs is shown in Table 7. [79][80][81][82][83][84][85][86][87] The effectiveness of FLU, ESC, and VEN as antidepressant therapy is reportedly associated with C3435T polymorphism, and their therapeutic effectiveness is higher in T allele carriers than C allele carriers, or the dose required for remission is lower in T allele carriers than C allele carriers. Because the P-gp expression is lower in T allele carriers than in non-T allele carriers as mentioned above, it is suggested that the association between C3435T polymorphism and antidepressant efficacy is due to (1) lower intestinal P-gp expression and consequently higher absorption ratio, higher plasma concentration, and higher efficacy in T allele carriers than in non-T allele carriers; and (2) lower BBB P-gp expression and consequently higher brain penetration and efficacy in T allele carriers than non-T allele carriers.…”

“…Furthermore, the effect of C3435T polymorphism on the PK of orally administered FLU was not significant. 84 Therefore, it is suggested that the effect of C3435T polymorphism on antidepressant drug efficacy was caused by decreased BBB P-gp expression. The C3435T polymorphisms did not affect the antidepressant efficacy of CIT and PAX.…”